Serine protease inhibitors-keto and di-keto containing ring systems

ABSTRACT

The present invention relates to certain substituted oxadiazole, thiadiazole and triazole peptoids which are useful as inhibitors of human neutrophil elastase (HNE) for the treatment of HNE-mediated processes implicated in conditions such as adult respiratory distress syndrome, septic shock and multiple organ failure. A series of studies also have indicated the involvement HNE in myocardial ischemia-reperfusion injury, emphysema. HNE-mediated processes are implicated in other conditions such as arthritis, periodontal disease, glomerulonephritis, dermatitis, psoriasis, cystic fibrosis, chronic bronchitis, atherosclerosis, Alzheimer&#39;s disease, organ transplantation, corneal ulcers, and invasion behavior of malignant tumors.

This application is a continuation-in-part of U.S. Ser. No. 08/345,820filed Nov. 21, 1994, now U.S. Pat. No. 5,618,792.

The present invention relates to certain substituted oxadiazole,thiadiazole and triazole peptoids which are useful as inhibitors ofserine proteases.

BACKGROUND OF THE INVENTION

The serine proteases are a class of enzymes which include elastase,chymotrypsin, cathepsin G, trypsin and thrombin. These proteases have incommon a catalytic triad consisting of Serine-195, Histidine-57 andAspartic acid-102 (chymotrypsin numbering system). Human neutrophilelastase (HNE) is a proteolytic enzyme secreted by polymorphonuclearleukocytes (PMNs) in response to a variety of inflammatory stimuli. Thisrelease of HNE and its extracellular proteolytic activity are highlyregulated and are normal, beneficial functions of PMNs. The degradativecapacity of HNE, under normal circumstances, is modulated by relativelyhigh plasma concentrations of α₁ -proteinase inhibitor (α₁ -PI).However, stimulated PMNs produce a burst of active oxygen metabolites,some of which (hypochlorous acid for example) are capable of oxidizing acritical methionine residue in α₁ -PI. Oxidized α₁ -PI has been shown tohave limited potency as an HNE inhibitor and it has been proposed thatalteration of this protease/antiprotease balance permits HNE to performits degradative functions in localized and controlled environments.

Despite this balance of protease/antiprotease activity, there areseveral human disease states in which a breakdown of this controlmechanism is implicated in the pathogenesis of the condition. Impropermodulation of HNE activity has been suggested as a contributing factorin adult respiratory distress syndrome, septic shock and multiple organfailure. A series of studies also have indicated the involvement of PMNsand neutrophil elastase in myocardial ischemia-reperfusion injury.Humans with below-normal levels of α₁ -PI have an increased probabilityof developing emphysema. HNE-mediated processes are implicated in otherconditions such as arthritis, periodontal disease, glomerulonephritis,dermatitis, psoriasis, cystic fibrosis, chronic bronchitis,atherosclerosis, Alzheimer's disease, organ transplantation, cornealulcers, and invasion behavior of malignant tumors.

There is a need for effective inhibitors of HNE as therapeutic and asprophylactic agents for the treatment and/or prevention ofelastase-mediated problems.

SUMMARY OF THE INVENTION

The present invention provides compounds which are useful as serineprotease inhibitors, including human neutrophil elastase. Thesecompounds are characterized by their relatively low molecular weight,high potency and selectivity with respect to HNE. They can be usedeffectively to prevent, alleviate or otherwise treat disease statescharacterized by the degradation of connective tissue by proteases inhumans.

The present invention provides compounds comprising oxadiazole,thiadiazole or triazole ring structures, and can be genericallydescribed by the formula: ##STR1## where X and Y are N, O or S;

Z is an α-amino carbonyl containing group; and

R₁ is a variable, both Z and R₁ being more fully described in parentapplication U.S. Ser. No. 08/345,820 (WO 96/16080), now U.S. Pat. No.5,618,792, the contents of which are incorporated in their entirety.

The present invention provides compounds preferably comprising1,2,4-oxadiazole (i.e., X is O; Y is N) or 1,3,4 oxadiazole rings (i.e.,X is N; Y is O). It has been found that compounds comprising 1,3,4oxadiazole ring structures possess improved inhibitory activity. Thepresent invention further provides compounds comprising various R₁ and Zsubstituents. The compounds of the present invention may be convenientlycategorized as Groups I through VI.

In one preferred embodiment, the invention provides compounds of theformula (Group I): ##STR2## wherein X and Y are O, N or S where at leastone of X or Y is N;

R₁ is alkyl or alkenyl, optionally substituted with halo or hydroxy;alkynyl, alkyl-C(O)OCH₃, dialkylamino, alkyldialkylamino; or cycloalkyl,alkylcycloalkyl, alkenylcycloalkyl, (C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl or(C₅ -C₁₂)arylalkenyl optionally comprising one or more heteroatomsselected from N, S, or non-peroxide O, and optionally substituted withhalo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamido, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamido,alkylthio or haloalkylthio;

R₂ and R₃ are independently or together H, alkyl, alkylthio,alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl, or phenyl alkyloptionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl,alkylthio, alkylguanidine, dialkylguanidine or amidine;

A is a direct bond, --C(O)--, --NH--C(O)--, --S(O)₂ --, --OC(O)--,--C--, or an amino acid selected from proline, isoleucine,cyclohexylalanine, cysteine optionally substituted at the sulfur withalkyl, alkenyl or phenyl optionally substituted with halogen, cyano,nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy,haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide,alkylthio, haloalkylthio; phenylalanine, indoline-2-carboxylic acid;tetrahydrosioquinoline-2-carboxylic acid optionally substituted withalkyl, alkenyl, haloalkenyl, alkynyl, halogen, cyano, nitro, haloalkyl,amino, aminoalkyl, dialkylamino, alkoxyl, haloalkoxy, carbonyl,carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio orhaloalkylthio; tryptophan, valine, norvaline, norleucine,octahydroindol-2-carboxylic acid, lysine optionally substituted at thenitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl,alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkylor cycloalkyl, bicycloalkyl, cycloalkyl alkyl, bicycloalkyl alkyl orfused aryl-cycloalkyl alkyl optionally comprising 1 or more heteroatomsselected from N, O and S; and

R₄ is H, alkyl, alkenyl, or cycloalkyl, aryl, arylalkyl or fusedaryl-cycloalkyl optionally comprising one or more heteroatoms selectedfrom N, O and S, and optionally substituted with alkyl, halo, alkoxy,amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy,carboalkoxy, alkylcarboxamido, aryl, arylcarboxamido, alkylthio orhaloalkylthio.

In a preferred embodiment, X is N and Y is O. In another preferredembodiment, X is O and Y is N. Preferably, R₄ --A is benzyloxycarbonyl.

Preferably, R₂ is isopropyl and R₃ is H.

In a preferred embodiment of the invention, R₁ is optionally substitutedbenzyl, preferably selected from methylbenzyl, 3,4-methylenedioxybenzylor trifluoromethylbenzyl. Alternatively, benzyl is substituted withdialkylamino, preferably dimethylamino. In yet another embodiment, R₁ ismethylenenaphthyl or an alkyl group, preferably methyl.

The present invention further provides compounds of the formula (GroupII): ##STR3## wherein X, Y, R₁, R₂ and R₃ are as described above;

B is --S(O)₂ -- or --C(O)--;

R₆ is ##STR4## where R'₂ and R'₃ are independently or together H, alkyl,alkylthio, alkylthioalkyl, or cycloalkyl, alkylcycloalkyl, phenyl orphenyl alkyl optionally substituted with guanidine, carboalkoxy,hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine, oramidine;

R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl,alkylthio, amino, alkylamino, dialkylamino, or aryl, fused aryl orcycloalkyl optionally comprising 1 or more heteroatoms selected from O,N and S, and optionally substituted with halo or alkyl;

R₁₄ is H, amino alkyl, alkenyl, or cycloalkyl, aryl, arylalkyl, or fusedarylcycloalkyl optionally comprising 1 or more heteroatoms selected fromN, O and S and optionally substituted with alkyl, halo, alkoxy, amino,alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy,carboalkoxy, alkylcarboxamido, aryl, arylcarboxamido, alkylthio orhaloalkylthio; and

R₁₅ is H, alkyl, halo, alkoxy, carboalkoxy, cycloakloxy, carboxyl,alkylthio, amino, alkylamino, dialkylamino, or aryl, fused aryl orcycloalkyl optionally comprising 1 or more heteroatoms selected from O,N, or S.

In a preferred embodiment, X is N and Y is O. In another preferredembodiment, X is O and Y is N. In a particular embodiment of theinvention, R₁₃ is phenyl, benzyl or H; R₁₄ is --NH₂ ; and R₁₅ is H.

Preferably, R₂ is isopropyl and R₃ is H.

In a preferred embodiment of the invention, R₁ is optionally substitutedbenzyl, preferably selected from methylbenzyl, 3,4-methylenedioxybenzylor trifluoromethylbenzyl. Alternatively, benzyl is substituted withdialkylamino, preferably dimethylamino. In yet another embodiment, R₁ ismethylenenaphthyl or an alkyl group, preferably methyl.

The present invention also provides compounds of the formula (GroupIII): ##STR5## wherein X, Y, R₁, R₂, R₃ and B are as described above;and

R₆ ##STR6## where m is 0 or 1; n is 0 or 1;

D is a direct bond or an amino acid selected from proline, isoleucine,cyclohexylalanine, cysteine optionally substituted at the sulfur withalkyl, alkenyl or phenyl optionally substituted with halogen, cyano,nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy,haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide,alkylthio, haloalkyl thio; phenylalanine, indoline-2-carboxylic acidtetrahydrosioquinoline-2-carboxylic acid optionally substituted withalkyl, alkenyl, haloalkenyl, alkynyl, halogen, cyano, nitro, haloalkyl,amino, aminoalkyl, dialkylamino, alkoxyl, haloalkoxy, carbonyl,carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio orhaloalkylthio; tryptophan, valine, norvaline, norleucine,octahydroindole-2-carboxylic acid, lysine optionally substituted at thenitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl,alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkylor cycloalkyl, bicycloalkyl, cycloalkyl alkyl, bicycloalkyl alkyl orfused aryl-cycloalkyl alkyl optionally comprising 1 or more heteroatomsselected from N, O and S;

A is a direct bond, --C(O)--, --NH--(C(O)--, --S(O)₂ --, --OC(O)-- or--C--; and

R₁₄ is H, alkyl, alkenyl or cycloalkyl, aryl, arylalkyl or fusedaryl-cycloalkyl optionally comprising 1 or more heteroatoms selectedfrom N, O and S, and optionally substituted with alkyl, halo, alkoxy,amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy,carboalkoxy, alkylcarboxamido, aryl, arylcarboxamido, alkylthio orhaloalkylthio.

Alternatively, R₆ is ##STR7## where W is S or O;

R₈ is alkylamino, dialkylamino or amino;

R₉ is H, alkyl or halo.

In a preferred embodiment, X is N and Y is O. In another preferredembodiment, X is O and Y is N. According to one embodiment, m is 1, n is0, and preferably, R₁₄ is benzyl, Z is --OC(O)-- and D is Val.

Preferably, R₂ is isopropyl and R₃ is H.

In a preferred embodiment of the invention, R₁ is optionally substitutedbenzyl, preferably selected from methylbenzyl, 3,4-methylenedioxybenzylor trifluoromethylbenzyl. Alternatively, benzyl is substituted withdialkylamino, preferably dimethylamino. In yet another embodiment, R₁ ismethylenenaphthyl or an alkyl group, preferably methyl.

The present invention further provides compounds of the formula (GroupIV): ##STR8## wherein X, Y, R₂ and R₃ are as described above;

R₁₀ is (C₅ -C₆)aryl, (C₅ -C₆)arylalkyl, (C₅ -C₆)arylalkenyl, cycloalkyl,arylcycloalkyl optionally comprising one or more heteroatoms selectedfrom N, S, or non-peroxide O, and optionally substituted with halo,cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamido, alkylthio or haloalkylthio;

D is a direct bond, --C(O), or an amino acid selected from proline,isoleucine, cyclohexylalanine, cysteine optionally substituted at thesulfur with alkyl, alkenyl or phenyl optionally substituted withhalogen, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino,alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide,arylcarboxamide, alkylthio, haloalkyl thio; phenylalanine,indoline-2-carboxylic acid, tetrahydroisoquinole-2-carboxylic acidoptionally substituted with alkyl, alkenyl, haloalkenyl, alkynyl,halogen, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino,alkoxyl, haloalkoxy, carbonyl, carboalkoxy, alkylcarboxamide,arylcarboxamide, alkylthio or haloalkylthio; tryptophan, valine,norvaline, norleucine, octahydroindole-2-carboxylic acid or lysineoptionally substituted at the nitrogen with alkyl, alkenyl, alkynyl,alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl,carboxyalkyl, alkoxycarbonyl alkyl or cycloalkyl, bicycloalkyl,cycloalkyl alkyl, bicycloalkyl alkyl or fused aryl-cycloalkyl alkyloptionally comprising 1 or more heteroatoms selected from N, O and S;

A is a direct bond, --C(O)--, --NH--C(O)--, --S(O)₂ --, --OC(O)NH--,--OC(O)-- or --C--; and R₁₄ is as described above.

In a preferred embodiment, X is N and Y is O. In another preferredembodiment, X is O and Y is N. Preferably, D is Val, A is --OC(O)-- andR₁₄ is benzyl. In a preferred embodiment, R₁₀ is (C₅ -C₆)aryl or (C₅-C₆)arylalkyl, preferably benzyl. According to another preferredembodiment, D is --C(O), and R₁₄ --A is pyrrole.

Preferably, R₂ is isopropyl and R₃ is H.

In a preferred embodiment of the invention, R₁ is optionally substitutedbenzyl, preferably selected from methylbenzyl, 3,4-methylenedioxybenzylor trifluoromethylbenzyl. Alternatively, benzyl is substituted withdialkylamino, preferably dimethylamino. In yet another embodiment, R₁ ismethylenenaphthyl or an alkyl group, preferably methyl.

The present invention additionally provides compounds of the formula(Group V): ##STR9## wherein X, Y, R₁, R₂, R₃, R'₂ and R'₃ are asdescribed above; and

R₁₁, R₁₂ and E together form a monocyclic or bicyclic ring comprising5-10 atoms selected from C, N, S and O; said ring containing 1 or moreketo groups; and optionally substituted with halo, cyano, nitro,haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido, alkylthio,haloalkylthio; cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C₅-C₁₂)aryl, (C₅ -C₁₂)arylalkyl, ((C₅ -C₁₂)arylalkyl)OC(O)NH-- or (C₅-C₁₂)arylalkenyl optionally comprising one or more heteroatoms selectedfrom N, S, or non-peroxide O, and optionally substituted with halo,cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,--C(O)O(alkyl), --C(O)(alkyl), alkylcarboxamido, alkylthio orhaloalkylthio.

In a preferred embodiment, X is N and Y is O. In another preferredembodiment, X is O and Y is N.

Preferably, R₂ is isopropyl and R₃ is H.

In a preferred embodiment of the invention, R₁ is optionally substitutedbenzyl, preferably selected from methylbenzyl, 3,4-methylenedioxybenzylor trifluoromethylbenzyl. Alternatively, benzyl is substituted withdialkylamino, preferably dimethylamino. In yet another embodiment, R₁ ismethylenenaphthyl or an alkyl group, preferably methyl.

According to one embodiment of the invention, R11, R12, and E togetherform a ring structure of formula (I): ##STR10## wherein A is asdescribed above; R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy,cycloakloxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, oraryl, fused aryl or cycloalkyl optionally comprising 1 or moreheteroatoms selected from O, N and S, and optionally substituted withhalo or alkyl; and

R₁₄ is H, alkyl, alkenyl or cycloalkyl, aryl, arylalkyl or fusedaryl-cycloalkyl optionally comprising 1 or more heteroatoms selectedfrom N, O and S, and optionally substituted with alkyl, halo, alkoxy,amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy,carboalkoxy, alkylcarboxamido, aryl, arylcarboxamido, alkylthio orhaloalkylthio.

Preferably, R₁₃ is halo; R₁₃ --A is CbzNH or H₂ N; and R'₂ and R'₃ areH.

In another embodiment, R₁₁, R₁₂ and E together form a ring of formula(II) ##STR11## wherein A, R₁₃ and R₁₄ are as described above;

Preferably, R'₂ and R'₃ are H. According to one embodiment, R₁₃ ispiperidinyl; and R₁₄ --A is CbzNH. Alternatively, R₁₃ is H; and R₁₄ --Ais amino, alkylamino or dialkylamino. In another preferred embodiment,R₁₃ is halo; and R₁₄ --A is CH₃ --O--C(O)--. In yet another embodiment,R₁₃ is H; and R₁₄ --A is CbzNH.

According to another embodiment of the invention, R₁₁, R₁₂ and E form aring of formula (III) or (IV): ##STR12## wherein A is a direct bond,--C-- or --C(O)--;

R₁₃, R₁₄ and R₁₅ are as defined above.

According to a particular embodiment, R₁₁, R₁₂ and E form a ring offormula (III); and --A--R₁₃ is --C(O)phenyl; R₁₄ is H; and R'₂ and R'₃are H.

In another embodiment, R₁₁, R₁₂ and E form a ring of formula (IV); and--A--R₁₃ is --C(O)phenyl; R₁₅ is H; and R'₂ and R'₃ are H.

In another embodiment of the invention, R11, R12 and E form a ring offormula (V): ##STR13## wherein W is S, SO or C;

n is 0, 1 or 2;

R₁₃ and R₁₄ are defined above; and

G is --NHC(O)--, --OC(O)NH--, --C(O)--, --NHS(O)₂ -- or a direct bond.

According to one embodiment, n is 0 and W is S, where preferably R₁₄ --Gis H. Preferably, R₁₃ is phenyl.

In another embodiment, n is 1 and W is C. Preferably, R₁₄ --G isCbzNH--. In a preferred embodiment, R₁₃ is phenyl substituted with halo.Preferably, R'₂ and R'₃ are H.

The invention further provides compounds wherein R₁₁, R₁₂ and E form aring of formulas (VI), (VII) or (VIII): ##STR14## wherein R₁₃ is asdefined above, or is ═CHR₁₅ or R₁₅ where R₁₅ is pyridinyl, phenyl orbenzyl optionally substituted with halo, dialkylamino or --C(O)OCH₃ ;

R₁₄ and R'₁₄ are independently or together H, alkyl, alkenyl, CH₃ C(O)--or cycloalkyl, aryl, arylalkyl or fused aryl-cycloalkyl optionallycomprising 1 or more heteroatoms selected from N, O and S, andoptionally substituted with alkyl, halo, alkoxy, amino, alkylamino,dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy,alkylcarboxamido, aryl, arylcarboxamido, alkylthio or haloalkylthio; and

R₁₆, R₁₇, R'₁₆ and R'₁₇ are independently or together H, alkyl,alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl orphenyl alkyl optionally substituted with guanidine, carboalkoxy,hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine oramidine.

Preferred compounds are of formula (VI) where R₁₃ is ═CHR₁₅ or R₁₅ ; andR₁₄ is H, alkyl, CH₃ C(O)-- or benzyl optionally substituted with alkyl,halo or alkylamino; and R'₂ and R'₃ are H. Preferably, R₁₃ is ═CHR₁₅where R₁₅ is phenyl optionally substituted with halo or --C(O)OCH₃.

In a further embodiment, R₁₁, R₁₂ and E form a ring of formula (IX):##STR15## wherein U, V, W and Y are independently or together N, C,C(O), N(R₁₃) where R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy,cycloakloxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, oraryl, fused aryl or cycloalkyl optionally comprising 1 or moreheteroatoms selected from O, N and S, and optionally substituted withhalo or alkyl; N(R₁₄) where R₁₄ is H, alkyl, alkenyl, or cycloalkyl,aryl, arylalkyl or fused aryl-cycloalkyl optionally comprising 1 or moreheteroatoms selected from N, O and S, and optionally substituted withalkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl,alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamido, aryl,arylcarboxamido, alkylthio or haloalkylthio; or C(R₁₆)(R₁₇) where R₁₆and R₁₇ are independently or together H, alkyl, alkylthio,alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyloptionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl,alkylthio, alkylguanidine, dialkylguanidine or amidine.

In one preferred embodiment, U is C(R₁₆)(R₁₇), V is N, W is N(R₁₄) and Yis C(O), where preferably R'₂ and R'₃ are H; R₁₆ is phenyl or benzyl;R₁₇ is H; and R₁₄ is H or benzyl optionally substituted with alkyl,halo, or alkylamine.

In another preferred embodiment, U is C(O), V is N, W is N(R₁₄) and Y isC(R₁₆)(R₁₇), where preferably R'₂ and R'₃ are H; R₁₄ is H; R₁₆ isphenyl; and R₁₇ is H.

In yet another preferred embodiment, U is C(O), V is N, W is N(R₁₄) andY is N(R₁₃), where preferably R'₂ and R'₃ are H; R₁₃ is phenyl; and R₁₄is H.

The invention further provides compounds of the formula (Group VI):##STR16## wherein X, Y, R₁, R₂, R₃, R₁₁, R₁₂ and E are as defined above.

Preferably, R₁₁, R₁₂ and E together form a ring of formula (X):##STR17## where U and V are independently or together N, C, N(R₁₃) whereR₁₃ is H, alkyl, alkoxy, carboalkoxy, cycloakloxy, carboxyl, alkylthio,amino, alkylamino, dialkylamino, or aryl, fused aryl or cycloalkyloptionally comprising 1 or more heteroatoms selected from O, N and S; orC(R₁₆)(R₁₇) where R₁₆ and R₁₇ are as defined above.

As used herein, the term "optionally substituted" means, whensubstituted, mono to fully substituted.

As used herein, the term "alkyl" means C₁ -C₁₅, however, preferably C₁-C₇.

As used herein, the term "alkenyl" means C₁ -C₁₅, however, preferably C₁-C₇.

As used herein, the term "alkynyl" means C₁ -C₁₅, however, preferably C₁-C₇.

It will be understood that alkyl, alkenyl and alkynyl groups, whethersubstituted or unsubstituted, may be linear or branched.

As used herein, the term "aryl", unless otherwise stated, means arylgroups preferably comprising 5 to 12 carbons, and more preferably 5 to 6carbons. As used herein, the term "arylalkyl" includes mono-substitutedalkyl groups (e.g., benzyl), as well as di-substituted alkyl groups suchas -alkyl(phenyl)₂ (e.g., --CH(phenyl)₂). As used herein, where the term"arylalkyl" is defined by the general formula (C_(x) -C_(y))arylalkyl, xand y refer to the number of carbons making up the aryl group. The alkylgroup is as defined above.

As used herein, the term "Cbz" means benzyloxycarbonyl.

Pharmaceutically acceptable salts of the compounds described above arewithin the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of the synthesis of compounds ofGroup I.

FIG. 2 is a schematic representation of the synthesis of compounds ofGroup I.

FIG. 3 is a schematic representation of the synthesis of compounds ofGroup I.

FIG. 4 is a schematic representation of the synthesis of compounds ofGroup I.

FIG. 5 is a schematic representation of the synthesis of compounds ofGroup II.

FIG. 6 is a schematic representation of the synthesis of compounds ofGroup II.

FIG. 7 is a schematic representation of the synthesis of compounds ofGroup II.

FIG. 8 is a schematic representation of the synthesis of compounds ofGroup III.

FIG. 9 is a schematic representation of the synthesis of compounds ofGroup III.

FIG. 10 is a schematic representation of the synthesis of compounds ofGroup IV.

FIG. 11 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 12 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 13 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 14 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 15 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 16 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 17 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 18 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 19 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 20 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 21 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 22 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 23 shows the activity of certain compounds of Group I.

FIG. 24 shows the activity of certain compounds of Group I.

FIG. 25 shows the activity of certain compounds of Group I.

FIG. 26 shows the activity of certain compounds of Group I.

FIG. 27 shows the activity of certain compounds of Group I.

FIG. 28 shows the activity of certain compounds of Groups II and III.

FIG. 29 shows the activity of certain compounds of Groups II, III andIV.

FIG. 30 shows the activity of certain compounds of Group V.

FIG. 31 shows the activity of certain compounds of Group V.

FIG. 32 shows the activity of certain compounds of Group V.

FIG. 33 shows the activity of certain compounds of Group V.

FIG. 34 shows the activity of certain compounds of Group V.

FIG. 35 shows the activity of certain compounds of Group V.

FIG. 36 shows the activity of certain compounds of Group V.

FIG. 37 shows the activity of certain compounds of Group V.

FIG. 38 shows the activity of certain compounds of Group V.

DETAILED DESCRIPTION

The compounds of the present invention have been found to be potentinhibitors of the serine protease human neutrophil elastase (HNE). Theyare reversible inhibitors that presumably form a transition stateintermediate with the active site serine residue. The compounds arecharacterized by their low molecular weight, high selectivity withrespect to HNE and stability regarding physiological conditions.Therefore, the compounds can be implemented to prevent, alleviate and/orotherwise treat diseases which are mediated by the degradative effectsassociated with the presence of HNE. Their usage is of particularimportance as they relate to various human treatment in vivo but mayalso be used as a diagnostic tool in vitro.

The compounds of the present invention are not limited to use forinhibition of human elastase. Elastase is a member of the class ofenzymes known as serine proteases. This class also includes, forexample, the enzymes chymotrypsin, cathepsin G, trypsin and thrombin.These proteases have in common a catalytic triad consisting ofSerine-195, Histidine-57 and Aspartic acid-102 (chymotrypsin numberingsystem). The precise hydrogen bond network that exists between theseamino acid residues allowing the Serine-195 hydroxyl to form atetrahedral intermediate with the carbonyl of an amide substrate. Thedecomposition of this intermediate results in the release of a freeamine and the acylated enzyme. In a subsequent step, this newly formedester is hydrolyzed to give the native enzyme and the carboxylic acid.It is this carboxyl component that helps characterize the specificityfor the enzyme. In the example in which the carboxyl component is apeptide, the alpha-substituted of the amino acid is predominatelyresponsible for the specificity toward the enzyme. Utilizing the wellaccepted subset nomenclature by Schechter and Berger (Biochem. Biophy.Res. Commun., 27, 157 (1967) and Biochem. Biophys. Res. Commun., 32, 898(1968)), the amino acid residues in the substrate that undergo thecleavage are defined as P₁ . . . P_(n) toward the N-terminus and P₁ ' .. . P_(n) ' toward the C-terminus. Therefore, the scissle bond isbetween the P₁ and the P₁ ' residue of the peptide subunits. A similarnomenclature is utilized for the amino acid residues of the enzyme thatmake up the binding pockets accommodating the subunits of the substrate.The difference is that the binding pocket for the enzyme is designatedby S₁ . . . S_(n) instead of P₁ . . . P_(n) as for the substrate.

The characteristics for the P₁ residue defining serine proteinasespecificity is well established. The proteinases may be segregated intothree subclasses: elastases, chymases and tryptases based on thesedifferences in the P₁ residues. The elastases prefer small aliphaticmoieties such as valine whereas the chymases and tryptases prefer largearomatic hydrophobic and positively charged residues respectively.

One additional proteinase that does not fall into one of thesecategories is prolyl endopeptidase. The P₁ residue defining thespecificity is a proline. This enzyme has been implicated in theprogression of memory loss in Alzheimer's patients. Inhibitorsconsisting of α-keto heterocycles have recently been shown to inhibitprolyl endopeptidase; Tsutsumi et al., J. Med. Chem., 37, 3492-3502(1994). By way of extension, α-keto heterocycles as defined by Formula Iallow for an increased binding in P' region of the enzyme.

                  TABLE 1    ______________________________________    P.sub.1 Characteristics for Proteinase Specificity    PROTEINASE             REPRESENTATIVE     P.sub.1    ______________________________________    Elastases             Human Neutrophil Elastase                                small aliphatic                                residues    Chymases alpha-Chymotrypsin, Cathepsin G                                aromatic or large                                hydrophobic                                residues    Tryptases             Thrombin, Tryptin, Urokinase,                                positively charged             Plasma Killikrein, Plasminogen                                residues             Activator, Plasmin    Other    Prolyl, Endopeptidase                                proline    ______________________________________

Since the P₁ residue predominately defines the specificity of thesubstrate, the present invention relates to P₁ -P_(n) ' modifications,specifically, certain alpha-substituted keto-heterocycles composed of 1,3, 4 oxadiazoles, 1, 2, 4-oxadiazoles, 1, 3, 4-thiadiazoles, 1, 2,4-thiadiazoles, 1-substituted, and 4-substituted 1,2,4-triazoles. Byaltering the alpha-substituted and the substituent on the heterocycle,the specificity of these compounds can be directed toward the desiredproteinase (e.g., small aliphatic groups for elastase).

The efficacy of the compounds for the treatment of various diseases canbe determined by scientific methods which are known in the art. Thefollowing are noted as examples for HNE mediated conditions:

for acute respiratory distress syndrome, the method according to Humanneutrophil elastase (HNE) model (AARD, 141, 227-677 (1990)), or theEndotoxin induced acute lung injury model in minipigs (AARD, 142,782-788 (1990)) may be used;

in ischemia/reperfusion, the method according to the canine model ofreperfusion injury (J. Clin. Invest., 81, 624-629 (1988)) may be used.

The compounds of the present invention, salts thereof, and theirintermediates can be prepared or manufactured as described herein or byvarious process known to be present in the chemical art (see also, WO96/16080). For example, compounds of Group I may be synthesizedaccording to FIGS. 1-2 (1,3,4 oxadiazoles) and FIGS. 3-4 (1,2,4oxadiazoles). FIGS. 5-7 describe the synthesis of compounds of Group II.FIGS. 8-9 describe the synthesis of compounds of Group III; FIG. 10describes synthesis of Group IV compounds. The several classes of GroupV compounds are described in FIGS. 11-22.

The activity of the compounds is presented in FIGS. 23-38 as K_(i)values (nm). K_(i) values were determined essentially as described in WO96/16080.

Although the compounds described herein and/or their its salts may beadministered as the pure chemicals, it is preferable to present theactive ingredient as a pharmaceutical composition. The invention thusfurther provides the use of a pharmaceutical composition comprising oneor more compounds and/or a pharmaceutical acceptable salt thereof,together with one or more pharmaceutically acceptable carriers thereforand, optionally, other therapeutic and/or prophylactic ingredients. Thecarrier(s) must be `acceptable` in the sense of being compatible withthe other ingredients of the composition and not deleterious to therecipient thereof.

Pharmaceutical compositions include those suitable for oral orparenteral (including intramuscular, subcutaneous and intravenous)administration. The compositions may, where appropriate, be convenientlypresented in discrete unit dosage forms and may be prepared by any ofthe methods well known in the art of pharmacy. Such methods include thestep of bringing into association the active compound with liquidcarriers, solid matrices, semi-solid carriers, finely divided solidcarriers or combination thereof, and then, if necessary, shaping theproduct into the desired delivery system.

Pharmaceutical compositions suitable for oral administration may bepresented as discrete unit dosage forms such as hard or soft gelatincapsules, cachets or tablets each containing a predetermined amount ofthe active ingredient; as a powder or as granules; as a solution, asuspension or as an emulsion. The active ingredient may also bepresented as a bolus, electuary or paste. Tablets and capsules for oraladministration may contain conventional excipients such as bindingagents, fillers, lubricants, disintegrants, or wetting agents. Thetablets may be coated according to methods well known in the art, e.g.,with enteric coatings.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may contain conventionaladditives such as suspending agents, emulsifying agents, non-aqueousvehicles (which may include edible oils), or preservative.

The compounds may also be formulated for parenteral administration(e.g., by injection, for example, bolus injection or continuousinfusion) and may be presented in unit dose form in ampules, pre-filledsyringes, small bolus infusion containers or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, andmay contain formulatory agents such as suspending, stabilizing and/ordispersing agents. Alternatively, the active ingredient may be in powderform, obtained by aseptic isolation of sterile solid or bylyophilization form solution, for constitution with a suitable vehicle,e.g., sterile, pyrogen-free water, before use.

For topical administration to the epidermis, the compounds may beformulated as ointments, creams or lotions, or as the active ingredientof a transdermal patch. Suitable transdermal delivery systems aredisclosed, for example, in Fischer et al. (U.S. Pat. No. 4,788,603) orBawas et al. (U.S. Pat. Nos. 4,931,279, 4,668,504 and 4,713,224).Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents. The active ingredient can also be delivered viaiontophoresis, e.g., as disclosed in U.S. Pat. Nos. 4,140,122,4,383,529, or 4,051,842.

Compositions suitable for topical administration in the mouth includeunit dosage forms such as lozenges comprising active ingredient in aflavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; mucoadherent gels, and mouthwashescomprising the active ingredient in a suitable liquid carrier.

When desired, the above-described composition can be adapted to providesustained release of the active ingredient employed, e.g., bycombination thereof with certain hydrophilic polymer matrices, e.g.,comprising natural gels, synthetic polymer gels or mixtures thereof.

The pharmaceutical compositions according to the invention may alsocontain other adjuvants such as flavorings, coloring, antimicrobialagents, or preservatives.

It will be further appreciated that the amount of the compound, or anactive salt or derivative thereof, required for use in treatment willvary not only with the particular salt selected but also with the routeof administration, the nature of the condition being treated and the ageand condition of the patient and will be ultimately at the discretion ofthe attendant physician or clinician.

In general, however, a suitable dose will be in the range of from about0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of bodyweight per day, such as 3 to about 50 mg per kilogram body weight of therecipient per day, preferably in the range of 6 to 90 mg/kg/day, mostpreferably in the range of 15 to 60 mg/kg/day.

The compounds is conveniently administered in unit dosage form; forexample, containing 5 to 1000 mg, conveniently 10 to 750 mg, mostconveniently, 50 to 500 mg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, most preferably, about 2 to about30 μM. This may be achieved, for example, by the intravenous injectionof a 0.05 to 5% solution of the active ingredient, optionally in saline,or orally administered as a bolus containing about 1-100 mg of theactive ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01-5.0 mg/kg/hr or byintermittent infusions containing about 0.4-15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention pertains and as may be applied to theessential features hereinbefore set forth, and as follows in the scopeof the appended claims.

The following examples are given to illustrate the invention and are notintended to be inclusive in any manner:

EXAMPLES Example 1 (CE-2072) (Benzyloxycarbonyl)-L-valyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

To a mixture containing 0.79 g (5.94 mmol) of N-chlorosuccinimide in 40mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.65 mL (8.85 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath, followed by the dropwiseaddition of a solution containing (benzyloxycarbonyl)-L-valyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!-L-prolinamide(0.90 g, 1.49 mmol) in 17 mL of anhydrous toluene. The reaction wasallowed to stir for 2 hours at -25° C. followed by the addition of 1.0mL (7.17 mmol) of triethylamine. The cold bath was removed and themixture allowed to warm to room temperature and maintained for 20minutes. The reaction mixture was diluted with ethyl acetate and washedwith water. The organic phase was dried over magnesium sulfate, filteredand the solvent removed under reduced pressure. The residue was purifiedby column chromatography on silica gel with 70% ethyl acetate/hexane togive 0.90 g of material which was further purified via preparative HPLCto afford 665 mg (73.9%) of the title compound as a white solid. FAB MSM+H! m/z; Calcd: 604, Found 604.

The intermediate (benzyloxycarbonyl)-L-valyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!-L-prolinamidewas prepared as follows:

a. 3-(S)-Amino-2-(R,S)-hydroxy-4-methyl pentanoic acid.

To a solution containing 3-(S)-benzyloxycarbonyl)amino!-2-acetoxy-4-methylpentanenitrile (see example 1of WO 96/16080) (15.2 g, 50.0 mmol) in 183 mL of dioxane was added 183mL of concentrated hydrochloric acid and 7.45 mL of anisole. Thereaction mixture was heated to reflux overnight. The hydrolysis reactionwas allowed to cool to room temperature and then concentrated in vacuo.The resulting aqueous solution was extracted with ether (2×). Theaqueous phase was placed on a Dowex 50X8-100 column (H+ form, preelutedwith deionized water to pH=7). The column was eluted with 2.0N ammoniumhydroxide and the pure fractions concentrated to afford 5.53 g (75%) of3-(S)-amino-2-(R,S)-hydroxy-4-methylpentanoic acid as a pale yellowsolid. FAB MS M+H! m/z; Calcd: 148, Found: 148.

b. 3-(S)- (Benzyloxycarbonyl)amino!-2-(R,S)-hydroxy-4-methylpentanoicacid.

To a solution under an atmosphere of nitrogen containing 1.0 g (6.8mmol) of 3-(S)-amino-2-(R,S)-hydroxy-4-methylpentanoic acid in 9.5 mL of1N NaOH and 10 mL of dioxane was added 1.43 g (8.4 mmol) of benzylchloroformate. The pH was maintained above pH 8 with 1N NaOH as needed.The reaction mixture was allowed to stir at room temperature overnight.The reaction was diluted with water and washed with ether. The aqueouslayer was acidified with 1N HCl to pH=2 and extracted with ether (2×).The combined organic layers were dried over magnesium sulfate, filteredand evaporated in vacuo to afford 1.75 g (92%) of 3-(S)-(benzyloxycarbonyl)amino!-2-(R,S)-hydroxy-4-methylpentanoic acid as alight yellow viscous oil. FAB MS M+H! m/z; Calcd: 282, Found 282.

c. 3-(S)- (Benzyloxylcarbonyl)amino!-2-(R,S)-acetoxy-4-methyl pentanoicacid.

To a solution of 3-(S)-(benzyloxycarbonyl)amino!-2-(R,S)-hydroxy-4-methylpentanoic acid 1.70 g,6.04 mmol) and pyridine (4.9 mL) was added acetic anhydride (5.7 mL,6.17 g, 60.4 mmol) dropwise at room temperature. The reaction wasallowed to stir overnight and was diluted with ethyl acetate and washedwith water (2×). The organic layer was dried over magnesium sulfate,filtered and evaporated in vacuo to give a thick oil. The residue waspurified by column chromatography on silica gel with 15%methanol/dichloromethane to afford 1.56 g (80%) of 3-(S)-(benzyloxycarbonyl)amino!-2-(R,S)-acetoxy-4-methyl pentanoic acid as alight yellow viscous oil. FAB MS M+H! m/z; Calcd: 324, Found: 324.

d. 1- (3-Methylphenylacetyl)-2-(2-(R,S)-acetoxy)-3-(S)-(benzyloxycarbonyl)amino!-4-methylpentanoyl!hydrazine.

To a solution containing 3-(S)-(benzyloxycarbonyl)amino!-2-(R,S)-acetoxy-4-methylpentanoic acid (2.3 g,7.11 mmol) in 40 mL of DMF under a nitrogen atmosphere at 0° C. wasadded 1.31 g (9.69 mmol) of HOBT and 1.36 g (7.09 mmol) of EDCI. Afterstirring for 30 minutes, 1.20 g (7.31 mmol) of 3-methylphenyl acetichydrazide (prepared analogously to the monoacid hydrazides cited byRabins et al. (J. Org. Chem, 1965, 30, 2486) and 1.0 mL (9.10 mmol) ofNMM were added. The reaction was allowed to warm to room temperature andstir overnight. The reaction was diluted with ethyl acetate and washedwith 5% potassium hydrogen sulfate, saturated sodium bicarbonate, brineand water. The organic phase was dried over magnesium sulfate, filteredand evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel with 10% methanol/dichloromethane toafford 2.31 g (89.0%) of the title compound as a white solid. FAB MSM+H! m/z; Calcd: 470, Found: 470.

e. 1- 2-(5- 3-Methylbenzyl)!-1,3,4-oxadiazolyl!-1-acetoxy-2-(S)-(benzyloxycarbonyl)amino!-3-methylbutane.

A solution containing 2.31 g (4.92 mmol) of 1-(3-methylphenylacetyl)-2-(2-(R,S)-acetoxy)-3-(S)-(benzyloxycarbonyl)amino!-4-methyl pentanoyl!hydrazine in 25 mL ofpyridine and 1.88 g (9.86 mmol) of toluene sulfonyl chloride was heatedat reflux under a nitrogen atmosphere for 72 hours. The solvent wasremoved under reduced pressure and the residue dissolved in ethylacetate and washed with water. The organic phase was dried overmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel with 5%ethyl acetate/hexane to afford 1.41 g (63.5%) of the title compound. FABMS M+H! m/z; Calcd: 452, Found: 452.

f. 1-!2-(5- 3-Methylbenzyl!-1,3,4-oxadiazolyl)!-2-(S)-(benzyloxycarbonyl)amino!-3-methylbutan-1-ol.

A solution containing 1.80 g (3.99 mmol) of 1- 2-(5-3-methylbenzyl!-1,3,4-oxadiazolyl)-1-acetoxy-2-(S)-(benzyloxycarbonyl)amino!-3-methylbutane and 0.72 g (5.21 mmol) ofpotassium carbonate in 30 mL of methanol and 8 mL of water was allowedto stir at room temperature for 30 minutes. The solvent was removedunder reduced pressure and the residue dissolved in ethyl acetate andwashed with water. The organic phase was dried over magnesium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel with 60% ethyl acetate/hexane toafford 1.46 (89.3%) of the title compound. FAB MS M+H! m/z; Calcd: 410,Found: 410.

g. 1- 2-(5-3-Methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-Amino-3-methylbutan-1-olhydrochloride.

To a solution containing 1.31 g (3.20 mmol) of 1- 2-(5-3-methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-(benzyloxycarbonyl)amino!-3-methylbutan-1-ol in 25 mL of trifluoroaceticacid under nitrogen atmosphere at 0° C. was added 0.43 mL (3.94 mmol) ofthioanisole. The reaction was allowed to warm to room temperatureovernight. The solvent was removed under reduced pressure and theresidue dissolved in ether and cooled to -78° C. under a nitrogenatmosphere. To this solution was added 3 mL (3 mmol) of 1N hydrochloricacid in ether. The resulting white solid was allowed to settle and theether decanted. Additional ether was added and decanted (3×). The solidwas dried under vacuum to afford 0.92 g (92.2%) of the title compound.FAB MS M+H! m/z; Calcd: 276, Found 276.

h. (Benzyloxycarbonyl)-L-valyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!-L-prolinamide.

To a solution containing 1.30 g (3.38 mmol) of Cbz-Val-Pro-OH in 25 mLof anhydrous dichloromethane under a nitrogen atmosphere at 0° C. wasadded 0.90 g (3.54 mmol) of BOPCl and 0.60 g (3.44 mmol) of DIEA. Afterstirring for 30 minutes, 0.90 g (2.89 mmol) of 1- 2-(5-3-methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methyl butan-1-olhydrochloride in 15 mL of dichloromethane and 0.6 mL (3.94 mmol) of DIEAwas added. The reaction was allowed to stir at 0° C. overnight. Thereaction was diluted with dichloromethane and washed with a saturatedsodium bicarbonate solution. The organic phase was dried over magnesiumsulfate, filtered and evaporated. The residue was purified by columnchromatography on silica gel with 6% methanol/dichloromethane to afford1.0 g (57.3%) of the title compound as a tan solid. FAB MS M+H! m/z;Calcd: 606, Found: 606.

Example 2 (CE-70)(Benzyloxycarbonyl)-L-valyl-N- 1-(2-5-(methyl)-1,3,4-oxadiazoly!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1. FAB M+H! m/z; Calcd: 514, Found 514.

Example 3 (CE-2075)(Benzyloxycarbonyl)-L-valyl-N- 1-(2-5-(3-trifluoromethylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1. FAB MS M+H! m/z; Calcd: 658, Found: 658.

Example 4 (CE-2100)(Benzyloxycarbonyl)-L-valyl-N- 1-(2-5-(4-Dimethylaminobenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1. FAB MS M+H! m/z; Calcd: 633, Found: 633.

Example 5 (CE-2124)(Benzyloxycarbonyl)-L-valyl-N- 1-(2-5-(1-naphthylenyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1. FAB MS M+H! m/z; Calcd: 640, Found: 640.

Example 6 (Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(3,4-methylenedioxybenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:634, Found 634.

Example 7 (CE-2052)(Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(3,5-dimethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:618, Found 618.

Example 8 (CE-2053)(Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(3,5-dimethoxybenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:650, Found 650.

Example 9 (CE-2054)(Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(3,5-ditrifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:726, Found 726.

Example 10 (CE-2055)(Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(3-methylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:604, Found 604.

Example 11 (CE-2057)(Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(biphenylmethine)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:666, Found 666.

Example 12 (CE-2058)(Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(4-phenylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:666, Found 666.

Example 13 (CE-2062)(Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(3-phenylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:666, Found 666.

Example 14 (CE-2066)(Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(3-phenoxybenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:682, Found 682.

Example 15 (CE-2069)(Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(cyclohexylmethylene)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:596, Found 596.

Example 16 (CE-2073)(Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(3-trifluoromethyldimethylene)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:686, Found 686.

Example 17 (CE-2077)(Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(1-naphthylmethylene)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:640, Found 640.

Example 18 (CE-2078)(Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(3-pyridylmethyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:591, Found 591.

Example 19 (CE-2096)(Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(3,5-diphenylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:742, Found 742.

Example 20 (CE-2115)(Benzyloxycarbonyl)-L-valyl-N- 1-(3-5-(4-dimethylaminobenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

Prepared similar to Example 1 of WO 96/16080. FAB MS M+H! m/z; Calcd:633, Found 633.

Example 21 (CE-2089) 2- 5-(Benzyloxycarbonyl)amino!-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!-N-1-(3-5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-(S)-2-methylpropyl!acetamide

To a mixture containing 1.15 g (8.60 mmol) of N-chlorosuccinimide in 43mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.95 mL (12.9 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry bath, followed by the dropwiseaddition of a solution containing 2- 5-(benzyloxycarbonyl)amino!-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!-N-1-(3-5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!hydroxymethyl)-(S)-2-methylpropyl!acetamide(1.52 g, 2.15 mmol) in 15 mL of anhydrous toluene. The reaction wasallowed to stir for 2 hours at -25° C. followed by the addition of 1.2mL (8.60 mmol) of triethylamine. The cold bath was removed and themixture allowed to warm to room temperature over 20 minutes. Thereaction mixture was diluted with ethyl acetate and washed with water.The organic phase was dried over magnesium sulfate, filtered andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel using a gradient elution of 2 to 10%methanol/dichloromethane to afford 1.19 g of material which was furtherpurified via preparative HPLC to afford 629 mg (41%) of the titlecompound as a white solid. FAB MS M+H! m/z; Calcd: 707, Found: 707.

The intermediate 2- 5-(benzyloxycarbonyl)amino!-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!-N-1-(3-5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!hydroxymethyl)-(S)-2-methylpropyl!acetamidewas prepared as follows: to a solution containing 1.35 g (3.7 mmol) of1- 3-5-(3-methylbenzyl)-1,2,4-oxadiazolyl!-2-(S)-amino-3-methylbutan-1-olhydrochloride and 5-(benzyloxycarbonyl)amino!-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!aceticacid (J. Med. Chem. 1995, 38, 98-108) in 10 mL of anhydrous DMF wasadded 1.0 mL (7.44 mmol) of TEA and 0.76 g (4.94 mmol) of HOBT. Themixture was cooled to 0° C. and 0.95 g (4.94 mmol) of EDC was added andthe reaction mixture was allowed to stir overnight. An additional 1.0 mL(7.44 mmol) of TEA was added and the reaction again allowed to stirovernight. The reaction was diluted with dichloromethane and washed witha saturated ammonium chloride solution (2×) and water. The organic phasewas dried over magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel with 2% methanol/dichloromethane to afford 1.52 g (87%) of the titlecompound. FAB MS M+H! m/z; Calcd: 709, Found: 709.

Example 22 (CE-2090) 2-5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!-N-1-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamid

To a mixture containing 0.41 g (0.58 mmol) of 2- 5-(benzyloxycarbonyl)amino!-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!-N-1-(3-5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-(S)-2-methylpropyl!acetamidein 4 mL of trifluoroacetic acid at room temperature under a nitrogenatmosphere was added 87 mg (0.70 mmol) of thioanisole. The reactionmixture was allowed to stir for 3 days and concentrated invacuo. Theresidue was purified via preparative HPLC to afford 269 mg (47%) of thetitle compound as a white solid. FAB MS M+H! m/z; Calcd: 573, Found:573.

Example 23 (CE-2095) 2- 5-(Benzyloxycarbonyl)amino!-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!-N-1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-(S)-2-methylpropyl!acetamide

To a mixture containing 0.83 g (6.23 mmol) of N-chlorosuccinimide in 32mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.7 mL (9.35 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath, followed by the dropwiseaddition of a solution containing 2- 5-(benzyloxycarbonyl)amino!-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!-N-1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-(S)-2-methylpropyl!acetamide(1.02 g, 1.56 mmol) in 12 mL of anhydrous toluene. The reaction wasallowed to stir for 2 hours at -25° C. followed by the addition of 0.9mL (6.23 mmol) of triethylamine. The cold bath was removed and themixture allowed to warm to room temperature over 20 minutes. Thereaction mixture was diluted with ethyl acetate and washed with water.The organic phase was dried over magnesium sulfate, filtered andevaporated. The residue was purified by column chromatography on silicagel using 1% methanol/dichloromethane to afford 1.37 g of material whichwas further purified via preparative HPLC to give 368 mg (36%) of thetitle compound as a white solid. FAB MS M+H! m/z; Calcd: 653, Found:653.

The intermediate 2- 5-(benzyloxycarbonyl)amino!-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!-N-1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-(S)-2-methylpropyl!acetamidewas prepared as follows: to a solution containing 1.35 g (3.7 mmol) of1- 2- 5-(3-methylbenzyl)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methyl butanehydrochloride and 5-(benzyloxycarbonyl)amino!-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!aceticacid (J. Med. Chem. 195, 38, 98-108) in 10 mL of anhydrous DMF was added0.73 mL (6.6 mmol) of NMM and 0.46 g (3.0 mmol) of HOBT. The mixture wascooled to 0° C. and 0.50 g (2.6 mmol) of EDCI was added and the reactionmixture was allowed to stir for 2 days. The reaction was diluted withdichloromethane and washed with a saturated ammonium chloride solution(2×) and water. The organic phase was dried over magnesium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel using a gradient elution of 2 to5% methanol/dichloromethane to afford 1.02 g (77%) of the titlecompound. FAB MS M+H! m/z; Calcd: 655, Found: 655.

Example 24 (CE-2101) 2-5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-methylpropyl!acetamide

To a mixture containing 0.219 g (0.335 mmol) of 2- 5 -(benzyloxycarbonyl)amino!-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!-N-1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-(S)-2-methylpropyl!acetamidein 3 mL of trifluoroacetic acid at room temperature under a nitrogenatmosphere was added 0.05 mL (0.402 mol) of thioanisole. The reactionmixture was allowed to stir for 3 days and concentrated invacuo. Theresidue was purified via preparative HPLC to afford 187 mg (88%) of thetitle compound as a white solid. FAB MS M+H! m/z; Calcd: 519, Found:519.

Example 25 (CE-2164)(Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!amide

To a mixture containing 1.97 g (14.7 mmol) of N-chlorosuccinimide on 60mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added1.54 mL (21.0 mmol) of dimethyl sulfide. The mixture was allowed to stirfor 1 hr. The reaction was cooled to -25° C. using a carbontetrachloride/dry ice bath, followed by the dropwise addition of asolution containing (0.90 g, 1.49 mmol) of(pyrrole-2-carbonyl)-N-(benzyl)glycyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)!-2-(S)-methylpropyl!amidein 30 mL of anhydrous toluene. The reaction was allowed to stir for 1hour at -25° C. followed by the addition of 2.16 mL (15.5 mL) oftriethylamine. The cold bath was removed and the mixture allowed to warmto room temperature over 20 minutes. The reaction mixture was dilutedwith ethyl acetate and washed with water. The organic phase was driedover magnesium sulfate, filtered and evaporated under reduced pressure.The residue was purified by column chromatography on silica gel withethyl acetate/hexane (4:1). The material was further purified viapreparative HPLC to afford 1.20 g (63.4%) of the title compound as awhite solid. FAB MS M+H! m/z; Cacld: 514, Found: 514.

The intermediate (pyrrole-2-carbonyl)-N-(benzyl)glycyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)!-2-(S)-methylpropyl!amidewas prepared by the following method:

a. (Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl ester.

To a suspension containing 3.00 g (27.0 mmol) of pyrrole-2-carboxylicacid in 75 mL of anhydrous dichloromethane under a nitrogen atmosphereat 0° C. was added 6.96 g (27.0 mmol of BOPCl and 14.1 mL (81.0 mmol) ofDIEA. After stirring for 30 minutes, 5.97 g (27.0 mmol) ofN-(benzyl)glycine-butyl ester was added and the reaction allowed to warmto room temperature overnight. The reaction was diluted with ethylacetate and washed with a 5% potassium hydrogensulfate, saturated sodiumbicarbonate solution and brine. The organic phase was dried overmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel using agradient of 100% hexane to 60% hexane/ethyl acetate to afford 2.92 g(34.4%) of the title compound is a white solid. FAB MS M+H! m/z Calcd:315, Found: 315.

b. (Pyrrole-2-carbonyl)-N-(benzyl)glycine.

To a solution containing 2.85 (9.01 mmol) of(Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl ester in 50 mL ofanhydrous dichloromethane cooled to 0° C. was added 25 mL of TFAdropwise. After 90 minutes an additional 25 mL of TFA was added andallowed to stir for 30 minutes. The mixture was evaporated in vacuo toafford 2.19 g of (Pyrole-2-carbonyl)-N-(benzyl)glycine as a tan solid.FAB MS M+H!m/z; Calcd. 259, Found 259.

c. (Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-(S)-2-methylpropyl!amide.

To a solution containing 1.90 g (7.35 mmol) of(Pyrrole-2-carbonyl)-N-(benzyl)glycine in 75 mL of anhydrous DMF wasadded 2.4 mL (22.1 mmol) of NMM and 1.29 g (9.56 mmol) of HOBT. Themixture was cooled to 0° C. and 1.69 g (8.82 mmol) of EDCI was added andthe reaction mixture was allowed to stir. After 30 minutes 2.17 g (6.99mmol) of 1- 2-(5-3-methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methyl butan-1-olhydrochloride in 25 mL of anhydrous DMF was added and the mixture wasallowed to warm to room temperature overnight. The reaction was dilutedwith ethyl acetate and washed with 5% potassium hydrogen sulfate andwater. The organic phase was dried over magnesium sulfate, filtered andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel using a gradient elution of 20 to 80% ethylacetate/hexane to afford 2.02 g (56%) of the title compound. FAB MS M+H!m/z Calcd: 516, Found: 516.

Example 26

(CE-2097)(Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-!1-(3-5-(3-trifluoromethylbenzyl)!-1,2,4-oxadiazolyl)-(S)-methylpropyl!amidewas prepared in a similar manner to Example 25. FAB MS M+H! m/z; Calcd:568, Found: 568.

Example 27 (CE-2130)(2S,5S)-5-Amino-1,2,4,5,6,7-hexahydroazepino-3,2,1!-indole-4-one-carbonyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-(R,S)-2-methylpropyl!amide

To a solution containing 0.93 g (1.28 mmol) of(2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino3,2,1!-indole-4-one-carbonyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-(S)-2-methylpropyl!amidein 4.5 mL of anhydrous DMF under an atmosphere of nitrogen was added0.45 mL of diethylamine. After stirring at room temperature for 15 minthe mixture was concentrated under high vacuum. The residue was purifiedvia preparative HPLC to afford 0.57 g (72%) of the title compound as awhite solid. FAB MS M+H! m/z; Calcd: 502, Found 502.

The intermediate (2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino3,2,1!-indole-4-one-carbonyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-(S)-2-methylpropyl!amidewas prepared as follows:

a. (2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino-3,2,1-indole-4-one-carbonyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-(S)-2-methylpropyl!amide.

To a solution containing 1.25 g (2.67 mmol) of(2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino3,2,1!indole-4-carboxylic acid in 200 mL of anhydrous dichloromethaneand 1 mL of anhydrous DMF under a nitrogen atmosphere at 0° C. was added0.71 g (2.80 mmol) of BOPCl and 0.6 mL (3.45 mmol) of DIEA. Afterstirring for 1 hr 1.14 g (3.66 mmol) of 1- 2-(5-3-methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL anhydrous dichloromethane was added and thereaction mixture allowed to stir at 4° C. overnight. The reaction wasdiluted with dichloromethane and washed with water. The organic phasewas dried over magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel using 3% methanol/dichloromethane to afford 1.30 g (67%) of thetitle compound as tan solid.

b. (2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino-3,2,1!-indole-4-one-carbonyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazole!carbonyl)!-(S)-2-methylpropyl!amide.

To a mixture containing 0.95 g (7.16 mmol) of N-chlorosuccinimide in 150mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.79 mL (10.7 mmol) of dimethyl sulfide. The mixture was allowed to stirfor 30 minutes. The reaction was cooled to -25° C. using a carbontetrachloride/dry ice bath, followed by the dropwise addition of asolution containing 1.30 g (1.79 mmol) of(2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino-3,2,1!-indole-4-one-carbonyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)!-(S)-2-methylpropyl!amidein 10 mL of anhydrous toluene. The reaction was allowed to stir for 2hours at -25° C. followed by the addition of 1.17 mL (8.4 mmol) oftriethylamine. The cold bath was removed and the mixture was allowed towarm to room temperature over 30 minutes. The reaction mixture wasdiluted with ethyl acetate and washed with water. The organic phase wasdried over magnesium sulfate. The residue was filtered, concentratedunder reduced pressure and purified by column chromatography on silicagel with 10% ethyl acetate/hexane to give 0.93 g (72%) as a tan foam.

Example 28 (CE-2126) BTD- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!amide

To a solution containing 0.41 g (0.59 mmol) of FMOC-BTD- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazole!carbonyl)-2-(S)-methylpropyl!amidein 4.5 mL of anhydrous DMF under an atmosphere of nitrogen was added 0.5mL of diethylamine. After stirring at room temperature for 30 min themixture concentrated under high vacuum. The residue was purified viapreparative HPLC to afford 0.23 g (66%) of the title compound as a whitesolid. FAB MS M+H! m/z; Calcd: 472, Found 472.

The intermediate Fmoc-BTD- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!amidewas prepared as follows:

a. (2S,5S)-Fmoc-BTD- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!amide.

To a solution containing 1.25 g (2.85 mmol) of FMOC-BTD in 80 mL ofanhydrous dichloromethane and 2.5 mL of anhydrous DMF under a nitrogenatmosphere at 0° C. was added 0.76 g (2.99 mmol) of BOPCl and 0.6 mL(3.45 mmol) of DIEA. After stirring for 30 minutes and 1.14 g (3.66mmol) of 1- 2-(5-3-methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methylbutan-1-olhydrochloride and 0.6 mL of DIEA in 10 mL of anhydrous dichloromethanewas added and the reaction mixture allowed to stir at 0° C. overnight.The reaction was diluted with dichloromethane and washed with water. Theorganic phase was dried over magnesium sulfate, filtered and evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel using 3% methanol/dichloromethane to afford1.13 g (55%) of the title compound as a tan foam.

b. Fmoc-BTD- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)!-2-(S)-methylpropyl!amide.

To a mixture containing 0.81 g (6.09 mmol) of N-chlorosuccinimide in 110mL of 1:1 anhydrous dichloromethane/toluene at 0° C. under a nitrogenatmosphere was added 0.67 mL (9.1 mmol) of dimethyl sulfide. The mixturewas allowed to stir for 30 minutes. The reaction was cooled to -25° C.using a carbon tetrachloride/dry ice bath, followed by the dropwiseaddition of a solution containing 1.06 g (1.52 mmol) of Fmoc-BTD- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!amidein 10 mL of anhydrous toluene. The reaction was allowed to stir for 2hours at -25° C. followed by the addition of 1.0 mL (7.6 mmol) oftriethylamine. The cold bath was removed and the mixture was allowed towarm to room temperature over 40 minutes. The reaction mixture wasdiluted with ethyl acetate and washed with water. The organic phase wasdried over magnesium sulfate. The resulting mixture was filtered,concentrated under reduced pressure and purified by columnchromatography on silica gel with 70% ethyl acetate/hexane to give 0.53g of the product as a yellow oil. The material was further purified bypreparative HPLC to afford 0.41 g (38.8%) of the title compound as awhite solid.

Example 29 (CE-2134)(R,S)-3-Amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N-1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

To a solution containing 0.93 g (1.19 mmol) of(R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamidein 5.0 mL of anhydrous DMF under an atmosphere of nitrogen was added0.45 mL of diethylamine. After stirring at room temperature for 2.5 hrthe mixture was concentrated under high vacuum. The residue was purifiedvia preparative HPLC to afford 0.030 g (4.5%) of the title compound as awhite solid. FAB MS M+H! m/z; Calcd: 565, Found: 565.

The intermediate(R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamidewas prepared as follows:

a. (R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamide.

To a solution containing 0.75 g (1.41 mmol) of(R,S)-FMOC-3-amino-N-1-carboxymethyl-2-oxo-5-phenyl-1,4,-benzodiazepinein 30 mL of anhydrous dichloromethane under a nitrogen atmosphere at 0°C. was added 0.36 g (1.41 mmol) of BOPCl and 0.25 mL (1.41 mmol) ofDIEA. After stirring for 1 hr 0.48 g (1.55 mmol) of 1- 2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methylbutan-1-olhydrochloride and 0.49 mL (2.82 mmol) of DIEA in 10 mL of anhydrousdichloromethane was added and the reaction mixture allowed to stir at 4°C. overnight. The reaction was diluted with ethyl acetate and washedwith water. The organic phase was dried over magnesium sulfate, filteredand evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel using a gradient of 2 to 6%methanol/dichloromethane to afford 1.00 g (89%) of the title compound asa yellow solid.

b. (R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide.

To a mixture containing 0.71 g (7.6 mmol) of N-chlorosuccinimide in 40mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.84 mL (11.4 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath followed by the dropwiseaddition of a solution containing 1.50 g (1.90 mmol) of(R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4-benzodiazepine-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamidein 10 mL of anhydrous toluene. The reaction was allowed to stir for 2hours at -25° C. followed by the addition of 1.0 mL 7.6 mmol) oftriethylamine. The cold bath was removed and the mixture was allowed towarm to room temperature over 1 hour. The reaction mixture was dilutedwith ethyl acetate and washed with water. The organic phase was driedover magnesium sulfate. The residue was filtered, concentrated underreduced pressure to afford 0.94 g (62%) of material which was usedwithout further purification. FAB MS M+H! m/z; Calcd: 787, Found: 787.

Example 30(CE-2145)(Benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N-1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!amide

To a mixture containing 0.48 g (3.67 mmol) of N-chlorosuccinimide in 30mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.40 mL (5.41 mmol) of dimethyl sulfide. After stirring for 1 hr thereaction mixture was cooled to -25° C. using a carbon tetrachloride/dryice bath followed by the dropwise addition of a solution containing 0.95g (1.90 mmol) of(benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!amidein 20 mL of anhydrous toluene. The reaction was allowed to stir for 2hours at -25° C. followed by the addition of 0.50 mL (3.6 mmol) oftriethylamine. The cold bath was removed and the mixture was allowed towarm to room temperature. The reaction mixture was diluted withdichloromethane and washed with 1N HCl (2×), saturated sodiumbicarbonate (2×) and water. The organic phase was dried over magnesiumsulfate. The mixture was filtered and concentrated under reducedpressure to afford 0.61 g. The residue was purified by columnchromatography on silica gel with 50% ethyl acetate/hexane to afford0.27 g of material which was further purified via preparative HPLC toafford 196 mg (33.4%) of the title compound as a white solid. FAB MSM+H! m/z Calcd: 652, Found 652.

The intermediate(benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!amidewas prepared by the following procedures:

a. 2-L-Methyl (2,3-dihydroindole)carboxylate.

To a suspension containing 5.00 g (30.6 mmol) of2-L-(2,3-dihydroindole)carboxylic acid in 100 mL of anhydrous MeOHcooled to 0° C. was added to a slow stream of HCl gas over 20 minutes.The resulting homogeneous solution was allowed to stir overnight warmingto room temperature. The mixture was evaporated and the residue wascrystallized from methanol/ether to afford, after drying, 5.58 g (85%)of 2-L-methyl (2,3-dihydroindole)carboxylate.

b. 2-Methyl (S)-1-(N-benzyloxycarbonyl!-L-valyl)-2,3-dihydro-1H-indole!carboxylate.

To a solution containing 3.00 g (14.0 mmol) ofmethyl(2,3-dihydroindole)-L-2-carboxylate in 60 mL of anhydrousdichloromethane, under a nitrogen atmosphere at 0° C., 7.15 g (28.8mmol) of BOPCl and 7.72 mL (70.2 mmol) of DIEA was added a solution of7.06 g (28.08 mmol) of Cbz-Val-OH in 40 mL of anhydrous dichloromethaneand 3 mL of DMF. After stirring for 3 days at 5° C. the mixture wasdiluted with ethyl acetate and washed with 1N HCl (2×) and brine. Themixture was filtered and evaporated under reduced pressure. The residuewas purified by column chromatography on silica gel using a gradient of9:1 to 1:1 hexane/ethyl acetate to afford 4.85 g (87%) of the titlecompound as a white foam.

c. 2- (S)-1-(N-Benzyloxycarbonyl!-L-valyl)-2,3-dihydro-1H-indole!carboxylicacid.

To a solution containing 4.85 g (12.17 mmol) of 2-methyl (S)-1-(N-benzyloxycarbonyl!-L-valyl)-2,3-dihydro-1H-indole!carboxylate in 45 mLof THF and 15 mL of MeOH at 0° C. was added 15.8 mL of 1N LiOH dropwise.After 30 minutes 1N HCl was added to pH 2 and the mixture extracted withethyl acetate (3×). The combined organic phases were dried overmagnesium sulfate, filtered and evaporated under reduced pressure toafford 4.51 g (93%) of the title compound as a white solid.

d. (Benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!amide.

To a solution containing 1.09 g (3.96 mmol) of 1- 2-(5-3-methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methylbutan-1-ol and1.31 g (3.3 mmol) of 2- (S)-1-(N-benzyloxycarbonyl!-L-valyl)-2,3-dihydro-1H-indole!carboxylic acid in 30mL of anhydrous dichloromethane was added 1.21 mL (6.93 mmol) of DIEAand 0.49 g (3.63 mmol) of HOBT. The mixture was cooled to 0° C. and 0.70g (3.63 mmol) of EDCI was added and the reaction mixture was allowed tostir overnight. An additional 1.0 mL (7.44 mmol) of TEA was added andthe reaction again allowed to stir overnight. The reaction was dilutedwith dichloromethane and washed with 1N HCl (2×), saturated sodiumbicarbonate (2×) and water. The organic phase was dried over magnesiumsulfate, filtered and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel with 80% ethylacetate/hexane to afford 0.66 g (30%) of the title compound.

Example 31(CE-2125)(Benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N-1-(3-5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!amide.

Prepared in a similar manner as in Example 30. FAB MS M+H! m/z; Calcd:706, Found: 706.

Example 32 (CE-2143) Acetyl-2-L-(2,3-dihydro-1H-indole)-N- 1-(3-5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!amide

Prepared in a similar manner as in Example 30. FAB MS M+H! m/z; Calcd:515, Found: 515.

Example 33 (CE-2165) Acetyl-2-L-(2,3-dihydro-1H-indole)-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!amide

Prepared in a similar manner as in Example 30. FAB MS M+H! m/z; Calcd:461, Found: 461.

Example 34 (CE-2104)(Morpholino-N-carbonyl)-L-valyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-L-prolinamide

To a mixture containing 0.69 g (5.17 mmol) of N-chlorosuccinimide in 60mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.60 mL (8.17 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath, followed by the additionof a solution containing (morpholino-N-carbonyl)-L-valyl-N- 1-(2-5-(3-methyl benzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S-)methylpropyl!-L-prolinamide (0.75 g, 1.28 mmol) in 10 mL of anhydrous toluene.The reaction was allowed to stir for 2 hours at -25° C. followed by theaddition of 1.1 mL (0.83 g, 7.89 mmol) of triethylamine. The cold bathwas removed and the reaction was allowed to warm to room temperatureover 20 minutes. The reaction was diluted with ethyl acetate and washedwith water. The organic phase was dried over magnesium sulfate andfiltered. The solvents were evaporated in vacuo and the residue purifiedby column chromatography, 70% ethyl acetate/hexane on silica gel. Finalpurification was performed by preparative HPLC to afford 405 mg (54.3%)of the title compound as a white solid. FAB MS M+H! m/z; Calcd: 583,Found: 583.

The intermediate (Morpholino-N-carbonyl)-L-valyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!-L-prolinamidewas prepared as follows:

a. (Morpholino-N-carbonyl)-L-valyl-L-proline-O-t-butyl ester.

To a solution containing L-valyl-L-proline-O-t-butyl-ester (1.80 g, 5.87mmol) in 80 mL of anhydrous methylene chloride and 1.5 mL (13.64 mmol)of N-methyl morpholine under a nitrogen atmosphere at 0° C. was addedmorpholine carbonyl chloride dropwise. The mixture was allowed to warmto room temperature overnight. The reaction was diluted with methylenechloride and washed with water. The organic layer was dried overmagnesium sulfate, filtered and evaporated. The residue was purified bycolumn chromatography on silica gel with 10% methanol/dichloromethane toafford 1.98 g (88%) of the title compound as a white solid. FAB MS M+H!m/z; Calcd: 384, Found: 384.

b. (Morpholino-N-carbonyl)-L-valyl-L-proline.

To a solution containing(morpholino-N-carbonyl)-L-valyl-L-proline-O-t-butyl ester (2.0 g, 5.22mmol) in 80 mL of anhydrous methylene chloride under a nitrogenatmosphere at 0° C. was added trifluoroacetic acid (13 mL, 130 mmol).The mixture was allowed to warm to room temperature overnight and thesolvents were evaporated in vacuo to give 2.26 g of a viscous oil. Thematerial was used without further purification.

c. (Morpholino-N-carbonyl)-L-valyl-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!-L-prolinamide.

To a solution containing 0.95 g (2.90 mmol) of(morpholino-N-carbonyl)-L-valyl-Proline in 25 mL of anhydrousdichloromethane under a nitrogen atmosphere at 0° C. was added 0.80 g(3.14 mmol) of BOPCI and 1.5 mL (8.61 mmol) of DIEA. After 30 minutes,0.75 g (2.41 mmol) of 1- 2-(5-3-methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL of dichloromethane and 1.1 mL (6.31 mmol) of DIEAwere added. The reaction was allowed to stir at 0° C. overnight. Thereaction was diluted with dichloromethane and washed with a saturatedNaHCO₃ solution. The organic phase was dried over magnesium sulfate andfiltered. The mixture was concentrated in vacuo and the residue purifiedby column chromatography on silica gel using 6% methanol/dichloromethaneto afford 0.77 g (54.84%) of the title compound as a white solid FAB MSM+H! m/z; Calcd: 585, Found: 585.

Example 35 (CE-2079) 3-(S)-(Benzyloxycarbonyl)amino)-ε-lactam-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

To a mixture containing 2.37 g (17.75 mmol) of N-chlorosuccinimide in100 mL of anhydrous toluene at 0° C. under a nitrogen atmosphere wasadded 1.94 mL (2.64 mmol) of dimethyl sulfide. The reaction was cooledto -25° C. using a carbon tetrachloride/dry ice bath, followed by thedropwise addition of a solution containing 2.5 g (4.44 mmol) of 3-(S)-(benzyloxycarbonyl)amino!-ε-lactam-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamide in 20 mL of anhydrous toluene. Upon complete addition,the reaction was to stirred at -25° C. for 2 hours, followed by theaddition of 3.0 mL (21.52 mmol) of triethylamine. The cold bath wasremoved and the reaction warmed to room temperature and stirred for 30minutes. The reaction was diluted with ethyl acetate and washed withwater. The organic phase was dried over magnesium sulfate. Filtration,removal of solvent and column chromatography of the residue on silicagel with 5% methanol/dichloromethane afforded 1.8 g of a pale yellowsolid. Subsequent preparative HPLC gave 950 mg (38.1%) of the titlecompound as a white solid. FAB MS M+H! m/z; Calcd: 562, Found: 562.

The intermediate 3-(S)- (benzyloxycarbonyl)amino!-ε-lactam-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamide was prepared as follows:

a. 3-(S)- (Benzyloxycarbonyl)amino!-ε-lactam.

To a mixture containing 9.9 g (37.18 mmol) of Cbz-ornithine in 150 mL ofacetronitrile under a nitrogen atmosphere was added 78 mL (369.70 mmol)of hexamethyldisilazane. The reaction was heated at reflux for 48 hours.The reaction mixture was cooled to room temperature and poured into 250mL of cold methanol. The solvent was removed under reduced pressure.Chloroform was added and the mixture filtered through a plug of celite.The filtrate was concentrated under reduced pressure an the residuedissolved in ethyl acetate. Hexane was added until the solution wasslightly turbid and then allowed to stand overnight. The resultant solidwas filtered and dried to afford 8.37 g (90.7%) of the title compound.

b. N- 3-(S)-(Benzyloxycarbonyl)amino!-ε-lactam-t-butyl acetate.

To a solution containing 1.0 g (4.03 mmol) of 3-(S)-(benzyloxylcarbonyl)amino!-ε-lactam in 20 mL of anhydrous DMF under anitrogen atmosphere was added 1.50 mL (10.16 mmol) of bromo-t-butylacetate and 1.17 g (5.05 mmol) of silver oxide. The reaction was heatedto 45° C. for 5 hours, diluted with acetronitrile and filtered through apad of celite. The filtrate was concentrated under reduced pressure andthe residue dissolved in ethyl acetate and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration, removal ofsolvent and column chromatography of the residue on silica gel with 60%ethyl acetate/hexane afforded 1.18 g (80.79%) of the title compound. FABMS M+H!m/z; Calcd: 363, Found: 363.

c. N- 3-(S)-(Benzyloxycarbonyl)amino)-ε-lactam-carboxymethane.

To a solution containing 0.55 g (1.52 mmol) of N- 3-(S)-(Benzyloxycarbonyl)amino!-ε-lactam-t-butyl acetate in 20 mL of dichloromethaneunder a nitrogen atmosphere at 0° C. was added 1.20 mL (15.58 mmol) oftrifluoroacetic acid. The reaction was allowed to warm to roomtemperature overnight. The solvent was removed under reduced pressure.The residue was dissolved in ether acetate and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration and removalof solvent afforded 0.50 of the title compound. FAB MS M+H! m/z; Calcd:307, Found: 307.

d. 3-(S)- Benzyloxycarbonyl)amino)-ε-lactam-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamide.

To a solution containing 2.72 g (8.88 mmol) of N-3-(S)-(Benzyloxycarbonyl)amino-ε-lactam-carboxymethane in 80 mL ofdichloromethane under a nitrogen atmosphere at 0° C. was added 2.37 g(9.31 mmol) of BOPCI and 1.60 mL (9.91 mmol) of DIEA. The reaction wasallowed to stir at 0° C. for 30 minutes followed by the addition of 2.37g (7.60 mmol) of 1- 2-(5-3-methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methyl butan-1-olhydrochloride in 20 mL of dichloromethane and 1.60 mL (9.19 mmol) ofDIEA. The reaction was allowed to stir at 0° C. overnight. The reactionwas diluted with dichloromethane and washed with water. The organicphase was dried over magnesium sulfate. Filtration, removal of solventand column chromatography of the residue on silica get with 10%methanol/dichloromethane afforded 2.58 g (50.23%) of the title compound.FAB MS M+H! m/z; Calcd: 564, Found: 564.

Example 36 (CE-2080) 3-(S)-(Amino)-ε-lactam-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamidetrifluoroacetic acid salt

This compound was prepared via deprotection of 3-(S)-benzyloxycarbonyl!amino-ε-lactam-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide under standard conditions to one skilled in the art toafford the title compound. FAB MS M+H! m/z; Calcd: 428, Found: 428.

Example 37 (CE-209) 3-(S)- (4-morpholinocarbonyl-butanoyl)amino!-ε-lactam-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(R,S)-methylpropyl!acetamide

To a solution containing 0.089 g (0.475 mmol) of 4-morpholino carbonylbutanoic acid in 10 mL of dichloromethane under a nitrogen atmosphere at0° C. was added 0.127 g (0.498 mmol) of BOPCI and 0.09 mL (0.492 mmol)of DIEA. The reaction was allowed to stir for 30 minutes followed by theaddition of 0.22 g (0.406 mmol) of 3-(S)-amino-ε-lactam-N- 1-(2-5-(3-methyl benzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(R,S)-methylpropyl!acetamide trifluoroacetic acid salt. The reaction was allowed tostir at 0° C. overnight. The reaction was diluted with dichloromethaneand washed with water. The organic phase was dried over magnesiumsulfate. Filtration, removal of solvent and purification via preparativeHPLC afforded 0.044 g (18%) of the title compound. FAB MS M+H! m/z;Calcd: 597, Found: 597.

Example 38 (CE-2087) 6- 4-Fluorophenyl!-ε-lactam-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

To a mixture containing 0.70 g (5.24 mmol) and N-chlorosuccinimide in 30mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.60 mL (8.17 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath, followed by the dropwiseaddition of a solution containing 0.67 g (1.32 mmol) of 6-4-fluorophenyl!-ε-lactam-N- 1-(2- 5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamide in15 mL of anhydrous toluene. Upon complete addition, the reaction wasallowed to stir at -25° C. for 2 hours followed by the addition of 0.90mL (6.46 mmol) of triethylamine. The cold bath was removed and thereaction allowed to warm to room temperature and maintained for 20 min.The reaction was diluted with ethyl acetate and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration, removal ofsolvent under reduced pressure and column chromatography of the residueon silica gel with 10% methanol/dichloromethane afforded 0.61 g of apale yellow solid. Subsequent preparative HPLC gave 338 mg (50.5%) ofthe title compound. FAB MS M+H! m/z; Calcd: 507, Found: 507.

The intermediate 6- 4-fluorophenyl!-ε-lactam-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamidewas prepared as follows:

a. 6- 4-Fluorophenyl!-6-carboxymethylene-2-piperidinone.

To a solution containing 2.15 g (8.11 mmol) of 6-4-fluorophenyl!-1-carbomethoxymethylene-2-piperidinone, prepared in asimilar fashion to that reported by Compernolle (Tetrahedron, 1993, 49,3193) in 70 mL of methanol and 20 mL of water under a nitrogenatmosphere was added 0.55 g (13.11 mmol) of lithium hydroxide. Thereaction was allowed to stir at room temperature for 2 hours. Thesolvent was removed under reduced pressure. The residue was diluted withwater and washed with ethyl acetate. The aqueous phase was acidifiedwith 1N hydrochloric acid and extracted with ethyl acetate. The organicphase was dried over magnesium sulfate. Filtration and removal ofsolvent afforded 2.0 g (98.2%) of the title compound. FAB MS M+H! m/z;Calcd: 252, Found: 252.

b. 6- 4-Fluorophenyl!-ε-lactam-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamide.

To a solution containing 1.04 g (4.14 mmol) of 6-4-fluorophenyl!-6-carboxymethylene-2-piperidinone in 25 mL of anhydrousdichloromethane under a nitrogen atmosphere at 0° C. was added 1.10 g(4.32 mmol) of BOPCI and 0.80 mL (4.59 mmol) of DIEA. After stirring for30 minutes, a solution containing 1.1 g (3.53 mmol) of 1- 2-(5-3-methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL of dichloromethane and 1.0 mL (6.31 mmol) ofDIEA. The reaction was allowed to stir at 0° C. overnight. The reactionwas diluted with dichloromethane and washed with a saturated sodiumbicarbonate solution. The organic phase wad dried over magnesiumsulfate. Filtration, removal of solvent under reduced pressure andcolumn chromatography of the residue on silica gel with 10%methanol/dichloromethane afforded 736 mg (41.0%) of the title compound.FAB MS M+H! m/z; Calcd: 509, Found: 509.

Example 39 (CE-2121) 2- 2-(R,S)-Phenyl-4-oxothiazolidin-3-yl!-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

To a mixture containing 2.05 g (15.38 mmol) of N-chlorosuccinimide in250 mL of anhydrous toluene at 0° C. under a nitrogen atmosphere wereadded 1.70 mL (23.06 mmol) of dimethyl sulfide. The reaction was cooledto -25° C. using a carbon tetrachloride/dry ice bath, followed byaddition of 1.90 g (3.84 mmol) of 2-2-(R,S)-phenyl-4-oxothiazolidin-3-yl!-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamidein 20 mL of anhydrous toluene dropwise. The reaction was allowed to stirat -25° C. for 2 hours, followed by the addition of 2.52 mL (18.07 mmol)of triethylamine. The cold bath was removed and the reaction allowed towarm to room temperature over 40 minutes. The reaction was diluted withethyl acetate and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent and columnchromatography of the residue on silica gel with 60% ethylacetate/hexane afforded 1.10 g of a yellow oil. Which was furtherpurified via preparative HPLC to give 0.45 g (24%) of the title compoundas an off-white solid. FAB MS M+H! m/z; Calcd: 493, Found: 493.

The intermediate 2- 2-(R,S)-phenyl-4-oxothiazolidin-3-yl!-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamidewas prepared as follows: to a solution containing 1.78 g (7.51 mmol) of2-(2-phenyl-4-oxothiazolidin-3-yl)acetic acid, prepared according toHolmes (J. Org. Chem, 1995, 60, 7328), in 80 mL of dichloromethane undera nitrogen atmosphere at 0° C. was added 2.04 g (8.02 mmol) of BOPCI and1.35 mL (7.76 mmol) of DIEA. After stirring for 30 minutes, 2.0 g (6.41mmol) of 1- 3-5-(3-methylbenzyl)!-1,3,4-oxadiazolyl!-2-(S)-amino-3-methyl-butan-1-olhydrochloride in 50 mL of dichloromethane and 1.35 mL (7.76 mmol) ofDIEA was added. The reaction was allowed to stir at 0° C. overnight. Thereaction mixture was diluted with dichloromethane and washed with water.The organic phase was dried over magnesium sulfate, filtered andconcentrated under reduced pressure. Column chromatography of theresidue on silica gel with 4% methanol/dichloromethane afforded 2.30 gof a yellow foam. Subsequent preparative HPLC gave 1.9 g of the titlecompound. FAB MS M+H! m/z; Calcd: 495, Found: 495.

Example 40

(CE-2122) 2- 2-(R,S)-Benzyl-4-oxothiazolidin-3-yl!-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-acetamidewas prepared in a similar manner as in Example 39. FAB MS M+H! m/z;Calcd: 507, Found: b 507.

Example 41 (CE-2136) 2- (2-(R,S),-Benzyl-4-oxothiazolidin-3-yl-oxide!-N-1-(2- 5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(R,S)-methylpropyl! acetamide

To a solution containing 1.31 g (2.59 mmol) of 2-2-(R,S)-benzyl-4-oxothiazolidin-3-yl)-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!-acetamide in 15 mL of methanol under a nitrogen atmosphere wasadded 0.51 mL (5.17 mmol) of 30% hydrogen peroxide. The reaction wasallowed to stir at room temperature overnight and then partitionedbetween brine and dichloromethane. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand column chromatography of the residue on silica gel with 85% ethylacetate/hexane afforded 0.73 g of a tan oil. Subsequent preparative HPLCgave 0.54 g (48%) of the title compound. FAB MS M+H! m/z; Calcd: 523,Found 523.

Example 42 (CE-2137) 2- 2-(R,S)-Benzyl-4-oxothiazolidin-3-yl oxide!-N-1-(3-5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl-2-(R,S,)-methylpropyl!acetamide

Prepared in a similar manner as in Example 41. FAB MS M+H! m/z; Calcd:577, Found 577.

Example 43 (CE-2118) 2- 2-(R,S)-Phenyl-4-oxometathiazan-3-yl!-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as in Example 39. FAB MS M+H! m/z; Calcd:507, Found 507.

Example 44 (CE-2140)(1-Benzoyl-3,8-quinazolinedione)-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

To a mixture containing 1.70 g (2.74 mmol) of N-chlorosuccinimide in 75mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added1.70 mL (23.15 mmol) of dimethyl sulfide. The reaction was cooled to-25° C. using a carbon tetrachloride/dry ice bath, followed by theaddition of 1.90 g (3.27 mmol) of (1-Benzoyl-3,8-quinazolinedione)-N-1-(2- 5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamide in 10 mL of toluene dropwise. The reaction was allowedto stir at -25° C. for 2 hours, followed by the addition of 3.20 mL(22.96 mmol) of triethylamine. The cold bath was removed and thereaction allowed to warm to room temperature and maintained for 15minutes. The reaction was diluted with ethyl acetate and washed withwater. The organic phase was dried over magnesium sulfate, filtered,and, and the solvent removed under reduced pressure. The residue waschromatographed on silica gel with 5% methanol/dichloromethane to afford1.37 g of a brown oil. This was further purified via preparative HPLC togive 450 mg (40.10%) of the title compound. FAB MS M+H! m/z; Calcd: 580,Found: 580.

The intermediate (1-benzoyl-3,8-quinazolinedione)-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamidewas prepared as follows:

a. 1-Benzoyl-3,8-quinazolinedione-2-t-butyl acetate.

To a solution containing 5.0 g (18.78 mmol) of1-Benzoyl-3,8-quinazolinedione prepared in a similar manner to thatreported by Melnyk et al. (Tetrahedron Lett., 1996, 37, 4145), in 100 mLof DMF under a nitrogen atmosphere was added 4.30 mL (29.12 mmol) ofbromo t-butylacetate and 5.4 (23.30 mmol) of silver oxide. The reactionwas heated to 50° C. overnight, diluted with ethyl acetate and washedwith water. The organic phase was dried over magnesium sulfate.Filtration, removal of solvent under reduced pressure and columnchromatography of the residue on silica gel with 40% ethylacetate/hexane gave 5.25 g (73.49%) of product. FAB MS M+H! m/z; Calcd:381, Found 381.

b. 1-Benzoyl-2-carboxymethylene-3,8-quinazolinedione.

To a solution containing 5.20 g (13.67 mmol) of1-benzoyl-3,8-quinazolinedione-2-t-butyl acetate in 300 mL ofdichloromethane under a nitrogen atmosphere at 0° C. was added 21.0 mL(211.44 mmol) of trifluoroacetic acid. The reaction was allowed to warmto room temperature overnight. The solvent was removed under reducedpressure and the residue dissolved in ethyl acetate and washed withwater. The organic phase was dried over magnesium sulfate. Filtrationand removal of solvent afforded 4.32 g (97.45%) of the title compound.FAB MS M+H! m/z; Calcd: 325, Found 325.

c. (1-Benzoyl-3,8-quinazolinedione)-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamide.

To a solution containing 1.80 g (5.55 mmol) of1-benzoyl-2-carboxymethylene-3,8-quinazolinedione in 100 mL of anhydrousdichloromethane and 5 mL of DMF under a nitrogen atmosphere at 0° C. wasadded 1.90 g (7.46 mmol) of BOPCI and 1.40 mL (8.05 mmol) of DIEA. Afterstirring for 30 minutes, a solution containing 1.70 g (5.45 mmol) of 1-2-(5- 3-methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methylbutan-1-olhydrochloride in 20 mL of dichloromethane and 3.80 mL (21.84 mmol) ofDIEA was added. The reaction was allowed to stir at 0° C. overnight,diluted with dichloromethane and washed with water. The organic phasewas dried over magnesium sulfate. Filtration, removal of solvent underreduced pressure and column chromatography of the residue on silica gelwith 10% methanol/dichloromethane afforded 1.93 (60.9%) of the titlecompound. FAB MS M+H! m/z; Calcd: 582, Found 582.

Example 45 (CE-2138)(1-Benzoyl-3,6-piperazinedione)-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as in Example 44. FAB MS M+H! m/z; Calcd:532, Found 532.

Example 46 (CE-2147)(1-Phenyl-3,6-piperazinedione)-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as in Example 44. FAB MS M+H! m/z; Calcd:504, Found 504.

Example 47 (CE-2148) (1-Phenyl-3,6-piperazinedione)-N- 1-(3-5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as in Example 44. FAB MS M+H! m/z; Calcd:558, Found 558.

Example 48 (CE-2108) 3- (Benzyloxycarbonyl)amino!-quinolin-2-one-N-1-(2-5-(3-methybenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

To a mixture containing 0.16 g (1.18 mmol) of N-chlorosuccinimide in 20mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.13 mL (1.77 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath followed by the addition ofa solution containing 0.18 g (0.30 mmol) of 3-(benzyloxycarbonyl)amino!-quinolin-2-one-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamidein 20 mL of methylene chloride dropwise. The reaction was allowed tostir at -25° C. for 2 hours, followed by the addition of 0.19 mL (1.38mmol) of triethylamine. The cold bath was removed and the reaction wasallowed to warm to room temperature and maintained for 30 minutes. Thereaction was diluted with ethyl acetate and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration, removal ofsolvent under reduced pressure and column chromatography of the residueon silica gel with 3% methanol/dichloromethane afforded 0.23 g of anoil. Further purification via preparative HPLC gave 100 mg of the titlecompound. FAB MS M+H! m/z; Calcd: 608, Found: 608

The intermediate 3- (benzyloxycarbonyl)amino!-quinolin-2-one-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamidewas prepared as follows:

a. 3- (Benzyloxycarbonyl)amino!-quinoline-2-one.

To a solution containing 0.5 g (3.10 mmol) of3-amino-quinolin-2-(1H)-one described by Anderson, et al. (J.Heterocyclic Chem., 193, 30, 1533) in 40 mL of dioxane under a nitrogenatmosphere was added 0.14 g (3.4 mmol) of sodium hydroxide in 14 mL ofwater. The reaction mixture was cooled to 0° C., followed by theaddition of 0.50 mL (3.4 mmol) of benzylchloroformate. The pH of thereaction was maintained above 8.0 with additional I N sodium hydroxide.The reaction was allowed to warm to room temperature and stirred for 2hours. The reaction was diluted with methylene chloride and washed withwater. The organic phase was dried over magnesium sulfate. Filtration,removal of solvent under reduced pressure and column chromatography ofthe residue on silica gel with 2% methanol/dichloromethane afforded 0.32g (35%) of product as a white solid. FAB MS M+H! m/z; Calcd: 295, Found:295

b. 3- (Benzylcarbonyl)amino!-quinolin-2-one-N-t-butyl-acetate.

To a solution containing 0.30 g (1.02 mmol) of 3-(benzyloxycarbonyl)amino!-quinolin-2-one in 20 mL of DMF under anitrogen atmosphere was added 0.15 mL (1.02 mmol) of t-butylbromoacetate and 0.24 g (1.02 mmol) of silver oxide. The reaction washeated to 70° C. and maintained overnight. The reaction mixture wasdiluted with acetronitrile and filtered through a pad of celite. Thefiltrate was concentrated under reduced pressure and the residuepartitioned between ethyl acetate and water. The organic phase was driedover magnesium sulfate. Filtration, removal of solvent under reducedpressure and column chromatography of the residue on silica gel withdichloromethane afforded 0.20 g (48%) of product as a white solid. FABMS M+H! m/z; Calcd: 409, Found: 409.

c. 3- (Benzyloxycarbonyl)amino!-1-carboxymethylene-quinolin-2-one.

To a solution containing 1.30 g (3.18 mmol) of 3-(benzyloxycarbonyl)amino!-quinolin-2-one-N-t-butyl-acetate in 35 mL ofdichloromethane under a nitrogen atmosphere at 0° C. was added 2.45 mL(31.84 mmol) of trifluoroacetic acid. The reaction was allowed to warmto room temperature overnight. The solvent was removed under reducedpressure to afford 1.09 g (97%) of the title compound. FAB MS M+H! m/z;Calcd: 353, Found: 353.

d. 3- (Benzyloxycarbonyl)amino!-quinolin-2-one-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamide.

To a solution containing 1.09 g (3.09 mmol) of 3-(benzyloxycarbonyl)amino!-1-carboxymethylene-quinolin-2-one in 50 mL ofanhydrous dichloromethane and 3 mL of DMF under a nitrogen atmosphere at0° C. was added 0.84 (3.31 mmol) of BOPCI and 1.10 mL (6.31 mmol) ofDIEA. After stirring for 30 minutes, 0.82 g (2.65 mmol) of 1- 2-(5-3-methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methylbutan-1-olhydrochloride in 8 mL of dichloromethane and 0.56 mL (3.20 mmol) of DIEAwas added. The reaction was allowed to stir at 0° C. overnight, dilutedwith dichloromethane and washed with water. The organic phase was driedover magnesium sulfate. Filtration, removal of solvent under reducedpressure and column chromatography of the residue on silica gel with 5%methanol/dichloromethane afforded 0.37 g (30.3%) of product. FAB MS M+H!m/z; Calcd: 610, Found: 610.

Example 49 (CE-2107) 3-(Benzyloxycarbonyl)amino!-7-piperidinyl-quinolin-2-one-N- 1-(2-5-(3-methybenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 48. FAB MS M+H! m/z;Calcd: 691, Found: 691.

Example 50 (CE-2117) 3-Carbomethoxy-quinolin-2-one-N- 1-(2-5-(3-methybenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 48. FAB MS M+H! m/z;Calcd: 535, Found: 535.

Example 51 (CE-2113) 3-(Amino-quinolin-2-one)-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

To a solution containing 2.30 g (3.79 mmol) of 3-(benzyloxycarbonyl)amino!-quinolin-2-one-N- 1-(2- 5-(3-methylbenzyl)-1,3,4-oxadiazolyl!-carbonyl)-2-(S)-methyl propyl acetamide in 60mL of trifluoroacetic acid under a nitrogen atmosphere at 0° C. wasadded 0.53 mL (4.54 mmol) of thioanisole. The reaction was allowed towarm to room temperature overnight. The solvent was removed underreduced pressure. Subsequent preparative HPLC afforded 0.61 g (27%); ofthe title compound. FAB MS M+H! m/z; Calcd: 474, Found: 474

Example 52 (CE-2116) 3- (4-Morpholino)aceto!amino-quinolin-2-one-N-1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

To a solution containing 0.32 g (1.22 mmol) of 4-morpholino acetic acidin 18 mL of dichloromethane under a nitrogen atmosphere at 0° C. wasadded 0.33 g (1.30 mmol) of BOPCI and 0.22 mL (1.26 mmol) of DIEA. Afterstirring for 1.5 hours, a solution containing 0.61 g (1.04 mmol) of3-(amino-quinolin-2-one)-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamidein 20 mL of dichloromethane was added followed by 0.22 mL (1.26 mmol) ofDIEA. The reaction was allowed to stir at 0° C. overnight, diluted withdichloromethane and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand preparative HPLC afforded 0.20 g (27%) of the title compound. FAB MSM+H! m/z; Calcd: 602, Found: 602

Example 53

(CE-2088) 3,4-Dihydro-quinolin-2-one-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamidefrom commercially available 3,4-Dihydro-2(1H)-quinolin-2-one. Preparedin a similar manner as shown in Example 52. FAB MS M+H! m/z; Calcd: 461,Found: 461

Example 54 (CE-2099) 1-Acetyl-3-benzylidene piperazine-2,5-dione-N-1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

To a solution containing 0.55 g (4.15 mmol) of N-chlorosuccinimide in 35mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.46 mL (6.22 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath, followed by the additionof a solution containing 0.58 g (1.04 mmol) of 1-acetyl-3-benzylidenepiperazine-2,5-dione-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamidein 8 mL of toluene. The reaction was allowed to stir at -25° C. for 2 h,followed by the addition of 0.68 mL (4.87 mmol) of triethylamine. Thecold bath was removed and the reaction allowed to warm to roomtemperature and maintained for 40 minutes. The reaction was partitionedbetween ethyl acetate and water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand column chromatography of the residue on silica gel 60% ethylacetate/hexane gave 0.54 g of a brown oil which was further purified viapreparative HPLC to give 146 mg (25%) of the title compound. FAB MS M+H!m/z; Calcd: 558, Found: 558

The intermediate 1-acetyl-3-benzylidene piperazine-2,5-dione-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamidewas prepared as follows:

a. 1-Acetyl-3-benzylidene piperazine-2,5-dione-N-t-butyl acetate.

To a solution containing 6.36 g (26.00 mmol) of 1-Acetyl-3-benzylidenepiperazine-2,5-dione described by D. Villemn, et al. (SyntheticCommunications, 1990, 20, 3325), in 100 mL of DMF under a nitrogenatmosphere was added 9.62 mL (65.10 mmol) of t-butyl bromoacetate and7.55 g (32.60 mmol) of silver oxide. The reaction was heated to 45° C.overnight. The reaction was filtered through a plug of celite and thefiltrate concentrated under reduced pressure. The residue was dilutedwith ethyl acetate and washed with water. The organic phase was driedover magnesium sulfate. Filtration, removal of solvent under reducedpressure and column chromatography of the residue on silica gel with 1%methanol/dichloromethane gave 5.37 g of a tan solid. Furtherpurification via preparative HPLC gave 2.5 g (27%) of the titlecompound. FAB MS M+H! m/z; Calcd: 359, Found: 359

b. 1-Acetyl-3-benzylidene-4-carboxymethylene-piperazine-2,5-dione.

To a solution containing 2.50 g (6.98 mmol) of 1-acetyl-3-benzylidenepiperazine-2,5-dione-N-t-butyl acetate in 100 mL of dichloromethaneunder a nitrogen atmosphere at 0° C. was added 5.40 mL (69.80 mmol) oftrifluoroacetic acid. The reaction was allowed to warm to roomtemperature overnight. The solvent was removed under reduced pressureand the residue diluted with ethyl acetate and washed with a saturatedsodium bicarbonate solution. The aqueous phase was acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The organic phasewas dried over magnesium sulfate. Filtration and removal of solventunder reduced pressure gave 1.96 g (96%) of product as at a solid. FABMS M+H! m/z; Calcd: 303, Found: 303

c. 1-Acetyl-3-benzylidene piperazine-2,5-dione-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamide.

To a solution containing 0.65 g (2.14 mmol) of1-acetyl-3-benzylidene-4-carboxymethylene-piperazine-2,5-dione in 40 mLof anhydrous dichloromethane and 3 mL of DMF under a nitrogen atmosphereat 0° C. was added 0.57 g (2.24 mmol) of BOPCl and 0.39 mL (2.21 mmol)of DIEA. After stirring for 30 minutes, a solution containing 0.57 g(1.83 mmol) of 1- 2-(5-3-methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL of dichloromethane and 0.39 mL (2.21 mmol) ofDIEA. The reaction was allowed to stir at 0° C. overnight, diluted withdichloromethane and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand column chromatography of the residue on silica gel with 5%methanol/dichloromethane gave 0.13 g (58%) of product. FAB MS M+H! m/z;Calcd: 560, Found: 560

Example 55 (CE-2105)1-Acetyl-3-(4-fluorobenzylidene)piperazine-2,5-dione-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 54. FAB MS M+H! m/z;Calcd: 576, Found: 576

Example 56 (CE-2111) 1-Acetyl-3-(4-dimethylaminobenzylidene)piperazine-2,5 -dione-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 54. FAB MS M+H! m/z;Calcd: 601, Found: 601.

Example 57 (CE-2112) 1-Acetyl-3-(4-carbomethoxybenzylidene)piperazine-2,5-dione-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 54. FAB MS M+H! m/z;Calcd: 616, Found: 616.

Example 58 (CE-2114) 1-Acetyl-3-(4-pyridyl)methylene!piperazine-2,5-dione-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 54. FAB MS M+H! m/z;Calcd: 559, Found: 559.

Example 59 (CE-2144) 4- 1-Benzyl-3-(R)-benzyl-piperazine-2,5,-dione!-N-1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

To a mixture containing 2.20 g (16.48 mmol) of N-chlorosuccinimide in100 mL of anhydrous toluene under a nitrogen atmosphere at 0° C. wasadded 2.1 mL (28.59 mmol) of dimethyl sulfide. The reaction was cooledto -25° C. using a carbon tetrachloride/dry ice bath, followed by theaddition of a solution containing 2.50 g (4.10 mmol) of 4-1-benzyl-3-(R)-benzyl piperazine-2,5,-dione!-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamidein 15 mL of toluene. The reaction was allowed to stir at -25° C. for 2hours, followed by the addition of 4.0 mL (28.70 mmol) of triethylamine.The cold bath was removed and the reaction allowed to warm to roomtemperature and maintained for 30 minutes. The reaction was diluted withethyl acetate and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reducedpressure, and column chromatography of the residue on silica gel with 5%methanol/dichloromethane afforded 2.27 g of a light brown solid whichwas further purified via preparative HPLC to give 350 mg (14.4%) of thetitle compound. FAB MS M+H! m/z; Calcd: 608, Found: 608

The intermediate 4- 1-benzyl-3-(R)-benzyl piperazine-2,5,-dione!-N-1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamidewas prepared as follows:

a. 1-Benzyl-3-(R)-benzyl piperazine-2,5-dione-4-t-butyl acetate.

To a solution containing 7.0 g (23.78 mmol) of 1-benzyl-3-(R)-benzylpiperazine-2,5-dione described by Steele, et al. (J. Biorg, Med. Chem.Lett., 1995, 5, 47) in 125 mL of DMF under a nitrogen atmosphere wasadded 5.30 mL (35.89 mmol) of t-butyl bromoacetate and 6.80 g (29.34mmol) of silver oxide. The reaction was heated to 50° C. overnight,diluted with ethyl acetate and washed with water. The organic phase wasdried over magnesium sulfate. Filtration, removal of solvent underreduced pressure and column chromatography of the residue on silica gelwith 50% ethyl acetate/hexane afforded 7.74 g (79.7%) of the titlecompound as a white solid. FAB MS M+H! m/z; Calcd: 409, Found: 409

b. 1-Benzyl-3-(R)-benzyl-4-carboxymethylene-piperazine-2,5-dione.

To a solution containing 7.70 g (18.85 mmol) of 1-Benzyl-3-(R)-benzylpiperazine-2,5-dione-4-t-butyl acetate in 300 mL of dichloromethaneunder a nitrogen atmosphere at 0° C. was added 19.0 mL (191.30 mmol) oftrifluoroacetic acid. The reaction was allowed to warm to roomtemperature overnight. The solvent was removed under reduced pressureand the residue dissolved in ethyl acetate and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration and removalof solvent under reduced pressure afforded 6.69 g of product. FAB MSM+H! m/z; Calcd: 353, Found: 353.

c. 4- 1-Benzyl-3(R)-benzyl piperazine-2,5,-dione!-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamide.

To a solution containing 2.0 g (5.68 mmol) of1-Benzyl-3-(R)-benzyl-4-carboxymethylene-piperazine-2,5-dione in 1000 mLof dichloromethane and 2 mL of DMF under a nitrogen atmosphere at 0° C.was added 2.0 g (7.86 mmol) of BOPCl and 1.50 mL (8.62 mmol) of DIEA.After stirring for 30 minutes, a solution containing 1.80 g (5.77 mmol)of 1- 2-(5-3-methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL of dichloromethane and 4.0 mL (22.99 mmol) ofDIEA. The reaction was allowed to stir at 0° C. overnight, diluted withdichloromethane and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand column chromatography of the residue on silica gel with 7%methanol/dichloromethane afforded 2.69 g (77.7%) of product. FAB MS M+H!m/z; Calcd: 610, Found: 610.

Example 60

(CE-2128) 4- 1-Benzyl-3-(S)-benzyl piperazine-2,5-dione!-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 59. FAB MS M+H! m/z;Calcd: 608, Found: 608.

Example 61 (CE-2146) 4- 1-Benzyl-3(R)-benzylpiperazine-2,5,-dione!-N-1-(3-5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 59. FAB MS M+H! m/z;Calcd: 662, Found: 662.

Example 62 (CE-2129) 4- 1-Benzyl-3-(S)-benzylpiperazine-2,5,-dione!-N-1-(3-5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 59. FAB MS M+H! m/z;Calcd: 662, Found: 662.

Example 63 (CE-2133) 4- 1-Benzyl-3-(S)-benzyl piperazine-2,5,-dione!-N-1-(3-5-(2-dimethylaminoethyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 59. FAB MS M+H! m/z;Calcd: 575, Found: 575.

Example 64 (CE-2084) 4- 1-Methyl-3-(R,S)-phenylpiperazine-2,5,-dione!-N-1-(3-5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 59. FAB MS M+H! m/z;Calcd: 572, Found: 572.

Example 65 (CE-2106) 4- 1-Methyl-3-(R,S)-phenylpiperazine-2,5,-dione!-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 59. FAB MS M+H! m/z;Calcd: 518, Found: 518.

Example 66 (CE-2162) 4- 1-(4-Morpholino ethyl)3-(R)-benzylpiperazine-2,5,-dione!-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 59. FAB MS M+H! m/z;Calcd: 631, Found: 631.

Example 67 (CE-2149) 5-(R,S)-Phenyl-2,4-imidazolidinedione-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

To a mixture containing 0.28 g (2.10 mmol) of N-chlorosuccinimide in 50mL of anhydrous toluene under a nitrogen atmosphere at 0° C. was added0.23 mL (3.13 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath, followed by the additionof a solution containing 0.26 g (0.52 mmol) of5-(R,S)-phenyl-2,4-imidazolidinedione-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamidein 10 mL of toluene. The reaction was allowed to stir at -25° C. for 2hours, followed by the addition of 0.30 mL (2.15 mmol) of triethylamine.The cold bath was removed and the reaction allowed to warm to roomtemperature and maintained for 30 minutes. The reaction was diluted withethyl acetate and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand column chromatography of the residue on silica gel with 10%methanol/dichloromethane, followed by preparative HPLC gave 120 mg(47.19%) of the title compound. FAB MS M+H! m/z; Calcd: 490, Found: 490

The intermediate 5-(R,S)-phenyl-2,4-imidazolidinedione-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamidewas prepared as follows:

a. (R)-N-(Ethoxy carbonylmethyl)-N'-(1-methoxy carbonyl-2-phenyl)urea

To a solution containing 18.45 g (91.49 mmol) of (R)-2-phenylglycinemethylester in 250 mL of ethyl acetate and 13.4 mL (96.13 mmol) oftriethylamine under a nitrogen atmosphere at 0° C. was added 10 mL(91.49 mmol) of ethyl isocyanatoacetate. After stirring for 1 h, thereaction was diluted with ethyl acetate and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration and removalof solvent under reduced pressure afforded 29.28 g (97.60%) of productas a white solid. FAB MS M+H! m/z; Calcd: 235, Found: 235.

b. (R)-5-Phenyl-3-carboxymethyl hydantoin.

A mixture containing 29.28 g (99.49 mmol of (R)-N-(ethoxycarbonylmethyl)-N'-(1-methoxy carbonyl-2-phenyl)urea in 500 mL ofconcentrated hydrochloric acid was heated to reflux overnight. Thereaction mixture was cooled to room temperature and extracted with ethylacetate. The organic phase was dried over magnesium sulfate. Filtrationand removal of solvent under reduced pressure afforded 14.01 g (60%) ofthe title compound. FAB MS M+H! m/z; Calcd: 295, Found: 295.

c. 5-(R,S)-Phenyl-2,4-imidazolidinedione-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!hydroxymethyl)-2-(S)-methylpropyl!acetamide.

To a solution containing 2.55 g (10.89 mmol) of(R)-5-phenyl-3-carboxymethyl hydantoin in 100 mL of dichloromethane and10 mL of DMF under a nitrogen atmosphere at 0° C. was added 2.30 g(12.00 mmol) of EDCI and 1.62 g (11.99 mmol) of HOBT. After stirring for30 minutes, a solution containing 4.43 g (14.21 mmol) of 1- 2-(5-3-methylbenzyl!)-1,3,4-oxadiazolyl!-2-(S)-amino-3-methylbutan-1-olhydrochloride in 20 mL of dichloromethane and 4.78 mL (43.50 mmol) ofNMM. The reaction was allowed to warm to room temperature overnight,diluted with dichloromethane and washed with water. The organic phasewas dried over magnesium sulfate. Filtration, removal of solvent underreduced pressure and column chromatography of the residue on silica gelwith 50% acetone/dichloromethane afforded 1.90 g (35.5%) of the titlecompound. FAB MS M+H! m/z; Calcd: 490, Found: 490.

Example 68 (CE-2154) 5-(R)-Benzyl-2,4-imidazolidinedione-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 67. FAB MS M+H! m/z;Calcd: 504, Found: 504.

Example 69 (CE-2142) 5-(S)-Benzyl-2,4-imidazolidinedione-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 67. FAB MS M+H! m/z;Calcd: 504, Found: 504.

Example 70 (CE-2141) 5-(S)-Benzyl-2,4-imidazolidinedione-N- 1-(3-5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 67. FAB MS M+H! m/z;Calcd: 558, Found: 558.

Example 71 (CE-2155) 5-(R)-Benzyl-2,4-imidazolidinedione-N- 1-(3-5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 67. FAB MS M+H! m/z;Calcd: 558, Found: 558.

Example 72 (CE-2151) 1-Benzyl-4-(R)-benzyl-2,5-imidazolidinedione-N-1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 67. FAB MS M+H! m/z;Calcd: 594, Found: 594.

Example 73 (CE-2150) 1-Benzyl-4-(R)-benzyl-2,5-imidazolidinedione-N-1-(3-5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide

Prepared in a similar manner as shown in Example 67. FAB MS M+H! m/z;Calcd: 648, Found: 648.

We claim:
 1. A compound of the formula ##STR18## wherein X and Y are O,N or S where at least one of X or Y is N;R₁ is alkyl or alkenyl,optionally substituted with halo or hydroxy; alkynyl, alkyl-C(O)OCH₃,dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, (C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl or (C₅-C₁₂)arylalkenyl optionally comprising one or more heteroatoms selectedfrom N, S, or non-peroxide O, and optionally substituted with halo,cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamido, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamido,alkylthio or haloalkylthio; R₂ and R₃ are independently or together H,alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenylor phenyl alkyl optionally substituted with guanidine, carboalkoxy,hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine oramidine; R'₂ and R'₃ are independently or together H, alkyl, alkylthio,alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyloptionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl,alkylthio, alkylguanidine, dialkylguanidine or amidine; and R₁₁, R₁₂ andE together form a monocyclic or bicyclic ring comprising 5-10 atomsselected from C, N, S and O; said ring containing 1 or more keto groups;and optionally substituted with halo, cyano, nitro, haloalkyl, amino,aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy,carboxyl, carboalkoxy, alkylcarboxamido, alkylthio, haloalkylthio;cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C₅ -C₁₂)aryl, (C₅-C₁₂)arylalkyl, ((C₅ -C₁₂)arylalkyl)OC(O)NH-- or (C₅ -C₁₂)arylalkenyloptionally comprising one or more heteroatoms selected from N, S, ornon-peroxide O, and optionally substituted with halo, cyano, nitro,haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, --C(O)O(alkyl),--C(O)(alkyl), alkylcarboxamido, alkylthio or haloalkylthio; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1wherein X is N and Y is O.
 3. The compound of claim 1 wherein X is O andY is N.
 4. The compound of claim 2 or 3 wherein R₂ is isopropyl and R₃is H.
 5. The compound of claim 4 wherein R₁ is optionally substitutedbenzyl.
 6. The compound of claim 5 wherein R₁ is methylbenzyl.
 7. Thecompound of claim 5 wherein R₁ is trifluoromethylbenzyl.
 8. The compoundof claim 5 wherein benzyl is substituted with dialkylamino.
 9. Thecompound of claim 8 wherein the dialkylamino is dimethylamine.
 10. Thecompound of claim 4 wherein R₁ is methylenenaphthyl.
 11. The compound ofclaim 4 wherein R₁ is methyl.
 12. The compound of claim 4 wherein R₁ is3,4-methylenedioxybenzyl.
 13. A compound of the formula: ##STR19##wherein X and Y are O, N or S where at least one of X or Y is N;R₁ isalkyl or alkenyl, optionally substituted with halo or hydroxy; alkynyl,alkyl-C(O)OCH₃, dialkylamino, alkyldialkylamino; or cycloalkyl,alkylcycloalkyl, alkenylcycloalkyl, (C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl or(C₅ -C₁₂)arylalkenyl optionally comprising one or more heteroatomsselected from N, S, or non-peroxide O, and optionally substituted withhalo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamido, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamido,alkylthio or haloalkylthio; R₂ and R₃ are independently or together H,alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenylor phenyl alkyl optionally substituted with guanidine, carboalkoxy,hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine oramidine; R'₂ and R'₃ are independently or together H, alkyl, alkylthio,alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyloptionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl,alkylthio, alkylguanidine, dialkylguanidine or amidine; A is a directbond, --C(O)--, --NH--C(O)--, --S(O)₂ --, --OC(O)--, --OC(O)NH--, --CH₂-- or --NH--; R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy,carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, fusedaryl or cycloalkyl optionally comprising 1 or more heteroatoms selectedfrom O, N and S, and optionally substituted with halo or alkyl; and R₁₄is H, alkyl, alkenyl or cycloalkyl, aryl, arylalkyl or fusedaryl-cycloalkyl optionally comprising 1 or more heteroatoms selectedfrom N, O and S, and optionally substituted with alkyl, halo, alkoxy,amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy,carboalkoxy, alkylcarboxamide, aryl, arylcarboxamido, alkylthio orhaloalkylthio; or a pharmaceutically acceptable salt thereof.
 14. Thecompound of claim 13 whereR₁₃ is halo; R₁₄ --A is CbzNH or H₂ N; and R'₂and R'₃ are H.
 15. A compound of the formula: ##STR20## wherein X and Yare O, N or S where at least one of X or Y is N;R₁ is alkyl or alkenyl,optionally substituted with halo or hydroxy; alkynyl, alkyl-C(O)OCH₃,dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, (C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl or (C₅-C₁₂)arylalkenyl optionally comprising one or more heteroatoms selectedfrom N, S, or non-peroxide O, and optionally substituted with halo,cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamido, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamido,alkylthio or haloalkylthio; R₂ and R₃ are independently or together H,alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenylor phenyl alkyl optionally substituted with guanidine, carboalkoxy,hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine oramidine; R'₂ and R'₃ are independently or together H, alkyl, alkylthio,alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyloptionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl,alkylthio, alkylguanidine, dialkylguanidine or amidine; A is a directbond, --C(O)--, --NH--C(O)--, --S(O)₂ --, --OC(O)--, --OC(O)NH--, --CH₂--, --NH-- or alkylamino; R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy,cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, oraryl, fused aryl or cycloalkyl optionally comprising 1 or moreheteroatoms selected from O, N and S, and optionally substituted withhalo or alkyl; and R₁₄ is H, alkyl, alkenyl or cycloalkyl, aryl,arylalkyl or fused aryl-cycloalkyl optionally comprising 1 or moreheteroatoms selected from N, O and S, and optionally substituted withalkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl,alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl,arylcarboxamido, alkylthio or haloalkylthio; or a pharmaceuticallyacceptable salt thereof.
 16. The compound of claim 15 whereR₁₃ ispiperidinyl; R₁₄ --A is CbzNH; and R'₂ and R'₃ are H.
 17. The compoundof claim 15 whereR₁₃ is H; and R₁₄ --A is amino, alkylamino ordialkylamino; and R'₂ and R'₃ are H.
 18. The compound of claim 15whereR₁₃ is halo; R₁₄ --A is CH₃ --O--C(O)--; and R'₂ and R'₃ are H. 19.The compound of claim 15 where p1 R₁₃ is H;R₁₄ --A is CbzNH--; and R'₂and R'₃ are H.
 20. A compound of the formula: ##STR21## wherein X and Yare O, N or S where at least one of X or Y is N;R₁ is alkyl or alkenyl,optionally substituted with halo or hydroxy; alkynyl, alkyl-C(O)OCH₃,dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, (C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl or (C₅-C₁₂)arylalkenyl optionally comprising one or more heteroatoms selectedfrom N, S, or non-peroxide O, and optionally substituted with halo,cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamido, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamido,alkylthio or haloalkylthio; R₂ and R₃ are independently or together H,alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenylor phenyl alkyl optionally substituted with guanidine, carboalkoxy,hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine oramidine; R'₂ and R'₃ are independently or together H, alkyl, alkylthio,alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyloptionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl,alkylthio, alkylguanidine, dialkylguanidine or amidine; A is a directbond, --C(O)--, or --CH₂ --; R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy,cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, oraryl, fused aryl or cycloalkyl optionally comprising 1 or moreheteroatoms selected from O, N and S, and optionally substituted withhalo or alkyl; and R₁₄ is H, alkyl, alkenyl or cycloalkyl, aryl,arylalkyl or fused aryl-cycloalkyl optionally comprising 1 or moreheteroatoms selected from N, O and S, and optionally substituted withalkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl,alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl,arylcarboxamido, alkylthio or haloalkylthio; and R₁₅ is H, alkyl, halo,alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino,alkylamino, dialkylamino or aryl, fused aryl or cycloalkyl optionallycomprising 1 or more heteroatoms selected from O, N and S; or apharmaceutically acceptable salt thereof.
 21. The compound of claim 20of the formula: ##STR22## wherein R₁₃ --A is --C(O)phenyl;R₁₄ is H; andR'₂ and R'₃ are H.
 22. The compound of claim 20 of the formula:##STR23## wherein R₁₃ --A is --C(O)phenyl;R₁₅ is H; and R'₂ and R'₃ areH.
 23. A compound of the formula: ##STR24## wherein X and Y is O, N or Swhere at least one of X or Y is N;R₁ is alkyl or alkenyl, optionallysubstituted with halo or hydroxyl; alkynyl, alkyl-C(O)OCH₃,dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, (C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl or (C₅-C₁₂)arylalkenyl optionally comprising one or more heteroatoms selectedfrom N, S, or non-peroxide O, and optionally substituted with halo,cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamide,alkylthio or haloalkylthio; R₂ and R₃ are independently or together H,alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenylor phenyl alkyl optionally substituted with guanidine, carboalkoxy,hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine oramidine; R'₂ and R'₃ are independently or together H, alkyl, alkylthio,alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyloptionally substituted with guanidine, carboalkoxy, hydroxyl, haloalkyl,alkylthio, alkylguanidine, dialkylguanidine or amidine; W is S, SO orCH₂ ; n is 0, 1 or 2; R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy,cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, oraryl, fused aryl or cycloalkyl optionally comprising 1 or moreheteroatoms selected from O, N and S, and optionally substituted withhalo or alkyl; R₁₄ is H, alkyl, alkenyl or cycloalkyl, aryl, arylalkylor fused aryl-cycloalkyl optionally comprising 1 or more heteroatomsselected from N, O and S, and optionally substituted with alkyl, halo,alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl,haloalkoxy, carboalkoxy, alkylcarboxamido, aryl, arylcarboxamido,alkylthio or haloalkylthio; and G is --NHC(O)--, --C(O)--, --OC(O)NH--,--NHS(O)₂ -- or a direct bond; or a pharmaceutically acceptable saltthereof.
 24. The compound of claim 23 wherein n is 0 and W is S.
 25. Thecompound of claim 24 wherein R₁₄ -G is H.
 26. The compound of claim 25wherein R₁₃ is phenyl.
 27. The compound of claim 23 wherein n is 1 and Wis --CH₂ --.
 28. The compound of claim 27 wherein R₁₄ --G is CbzNH--.29. The compound of claim 28 wherein R₁₃ is phenyl substituted withhalo.
 30. The compound of claim 28 wherein R'₂ and R'₃ are H.
 31. Acompound of the formula: ##STR25## wherein X and Y is O, N or S where atleast one of X or Y is N;R₁ is alkyl or alkenyl, optionally substitutedwith halo or hydroxyl; alkynyl, alkyl-C(O)OCH₃, dialkylamino,alkyldialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl,(C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl or (C₅ -C₁₂)arylalkenyl optionallycomprising one or more heteroatoms selected from N, S, or non-peroxideO, and optionally substituted with halo, cyano, nitro, haloalkyl, amino,aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy,carboxyl, carboalkoxy, alkylcarboxamide, (C₅ -C₆)aryl, --O--(C₅-C₆)aryl, arylcarboxamide, alkylthio or haloalkylthio; R₂ and R₃ areindependently or together H, alkyl, alkylthio, alkylthioalkyl orcycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionallysubstituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio,alkylguanidine, dialkylguanidine or amidine; R'₂ and R'₃ areindependently or together H, alkyl, alkylthio, alkylthioalkyl orcycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionallysubstituted with guanidine, carboalkoxy, hydroxyl, haloalkyl, alkylthio,alkylguanidine, dialkylguanidine or amidine; R₁₃ is H, alkyl, halo,alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino,alkylamino, dialkylamino, or aryl, fused aryl or cycloalkyl optionallycomprising 1 or more heteroatoms selected from O, N and S, andoptionally substituted with halo or alkyl; or ═CHR₁₅ or R₁₅ where R₁₅ ispyridinyl, phenyl or benzyl optionally substituted with halo,dialkylamino, or --C(O)OCH₃ ; R₁₄ and R'₁₄ are independently or togetherH, alkyl, alkenyl, CH₃ C(O)-- or cycloalkyl, aryl, arylalkyl or fusedaryl-cycloalkyl optionally comprising 1 or more heteroatoms selectedfrom N, O and S, and optionally substituted with alkyl, halo, alkoxy,amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy,carboalkoxy, alkylcarboxamido, aryl, arylcarboxamido, alkylthio orhaloalkylthio; and R₁₆, R₁₇, R'₁₆ and R'₁₇ are independently or togetherH, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl,phenyl or phenyl alkyl optionally substituted with guanidine,carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine,dialkylguanidine or amidine; or a pharmaceutically acceptable saltthereof.
 32. A compound of claim 31 of formula: ##STR26## wherein R₁₃ is═CHR₁₅ or R₁₅ ;R₁₄ is H, alkyl, CH₃ C(O)-- or benzyl optionallysubstituted with alkyl, halo or alkylamino; and R'₂ and R'₃ are H. 33.The compound of claim 32 whereR₁₃ is ═CHR₁₅ and R₁₅ is phenyl optionallysubstituted with halo or --C(O)OCH₃.
 34. A compound of the formula:##STR27## wherein X and Y are O, N or S where at least one of X or Y isN;R₁ is alkyl or alkenyl, optionally substituted with halo or hydroxy;alkynyl, alkyl-C(O)OCH₃, dialkylamino, alkyldialkylamino; or cycloalkyl,alkylcycloalkyl, alkenylcycloalkyl, (C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl or(C₅ -C₁₂)arylalkenyl optionally comprising one or more heteroatomsselected from N, S, or non-peroxide O, and optionally substituted withhalo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamido, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamido,alkylthio or haloalkylthio; R₂ and R₃ are independently or together H,alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenylor phenyl alkyl optionally substituted with guanidine, carboalkoxy,hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine oramidine; R'₂ and R'₃ are independently or together H, alkyl, alkylthio,alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyloptionally substituted with guanidine, carboalkoxy, hydroxyl, haloalkyl,alkylthio, alkylguanidine, dialkylguanidine or amidine; V is N or C; andU, W and Y are independently or together N, C, C(O), N(R₁₃) where R₁₃ isH, alkyl, halo, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino,alkylamino, dialkylamino, or aryl, fused aryl or cycloalkyl optionallycomprising 1 or more heteroatoms selected from O, N, and S, andoptionally substituted with halo or alkyl; N(R₁₄) where R₁₄ is H, alkyl,alkenyl, or cycloalkyl, aryl, arylalkyl or fused arylcycloalkyloptionally comprising 1 or more heteroatoms selected from N, O and S,and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino,dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy,alkylcarboxamide, aryl, arylcarboxamide, alkylthio or haloalkylthio; orC(R₁₆)(R₁₇) where R₁₆ and R₁₇ are independently or together H, alkyl,alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl orphenyl alkyl optionally substituted with guanidine, carboalkoxy,hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine oramidine.
 35. The compound of claim 34 wherein U is C(R₁₆)(R₁₇), V is N,W is N(R₁₄) and Y is C(O).
 36. The compound of claim 35 whereR'₂ and R'₃are H; R₁₆ is phenyl or benzyl; R₁₇ is H; and R₁₄ is H or benzyloptionally substituted with alkyl, halo, or alkylamine.
 37. The compoundof claim 34 where U is C(O), V is N, W is N(R₁₄) and Y is C(R₁₆)(R₁₇).38. The compound of claim 37 whereinR'₂ and R'₃ are H; R₁₄ is H; R₁₆ isphenyl; and R₁₇ is H.
 39. The compound of claim 34 where U is C(O), V isN, W is N(R₁₄) and Y is N(R₁₃).
 40. The compound of claim 39 whereR'₂and R'₃ are H; R₁₃ is phenyl; and R₁₄ is H.
 41. A compound of theformula ##STR28## wherein X and Y are O, N or S where at least one of Xor Y is N;R₁ is alkyl or alkenyl, optionally substituted with halo orhydroxy; alkynyl, alkyl-C(O)OCH₃, dialkylamino, alkyldialkylamino; orcycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C₅ -C₁₂)aryl, (C₅-C₁₂)arylalkyl or (C₅ -C₁₂)arylalkenyl optionally comprising one or moreheteroatoms selected from N, S, or non-peroxide O, and optionallysubstituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,carboalkoxy, alkylcarboxamido, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl,arylcarboxamido, alkylthio or haloalkylthio; R₂ and R₃ are independentlyor together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl,alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted withguanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine,dialkylguanidine or amidine; and R₁₁, R₁₂ and E together form amonocyclic or bicyclic ring comprising 5-10 atoms selected from C, N, Sand O; said ring containing 1 or more keto groups; and optionallysubstituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,carboalkoxy, alkylcarboxamido, alkylthio, haloalkylthio, cycloalkyl,alkylcycloalkyl, alkenylcycloalkyl, (C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl,((C₅ -C₁₂)arylalkyl)OC(O)NH-- or (C₅ -C₁₂)arylalkenyl optionallycomprising one or more heteroatoms selected from N, S, or non-peroxideO, and optionally substituted with halo, cyano, nitro, haloalkyl, amino,aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy,carboxyl, carboalkoxy, --C(O)O(alkyl), --C(O)(alkyl), alkylcarboxamido,alkylthio or haloalkylthio; or a pharmaceutically acceptable saltthereof.
 42. A compound of the formula: ##STR29## wherein X and Y is O,N or S where at least one of X or Y is N;R₁ is alkyl or alkenyl,optionally substituted with halo or hydroxyl; alkynyl, alkyl-C(O)OCH₃,dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, (C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl or (C₅-C₁₂)arylalkenyl optionally comprising one or more heteroatoms selectedfrom N, S, or non-peroxide O, and optionally substituted with halo,cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamide,alkylthio or haloalkylthio; R₂ and R₃ are independently or together H,alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenylor phenyl alkyl optionally substituted with guanidine, carboalkoxy,hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine oramidine; R'₂ and R'₃ are independently or together H, alkyl, alkylthio,alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyloptionally substituted with guanidine, carboalkoxy, hydroxyl, haloalkyl,alkylthio, alkylguanidine, dialkylguanidine or amidine; U and V areindependently or together N, C, N(R₁₃) where R₁₃ is H, alkyl, alkoxy,carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino,dialkylamino, or aryl, fused aryl or cycloalkyl optionally comprising 1or more heteroatoms selected from O, N, and S, and optionallysubstituted with halo or alkyl; or C(R₁₆)(R₁₇) where R₁₆ and R₁₇ areindependently or together H, alkyl, alkylthio, alkylthioalkyl orcycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionallysubstituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio,alkylguanidine, dialkylguanidine or amidine; and n is 1 or 2; or apharmaceutically acceptable salt thereof.
 43. A method of inhibiting atleast one serine protease comprising administering to a host in need ofsuch inhibition an effective amount of a compound of claim 1, 13, 15,20, 23, 31, 34, 41 or
 42. 44. The method of claim 43 wherein the serineprotease is elastase.
 45. The method of claim 44 wherein the elastase ishuman neutrophil elastase.
 46. The compound of claim 14 wherein R₁ isoptionally substituted benzyl.
 47. The compound of claim 46 wherein R₁is methylbenzyl or trifluoromethylbenzyl.
 48. The compound of claim 47wherein R₂ and R₃ are alkyl or H.
 49. The compound of claim 48 whereinR₂ is isopropyl and R₃ is H.
 50. The compound of claim 49 wherein X is Nand Y is O; or X is O and Y is N.
 51. The compound of claim 50 whereinR₁₃ is F.
 52. The compound of claim 51, of the formula:

    2- 5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!-N- 1-(3- 5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide.


53. The compound of claim 51, of the formula:

    2- 5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!-N- 1-(2- 5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide.


54. 54. The compound of claim 13 wherein X is N and Y is O.
 55. Thecompound of claim 13 wherein X is O and Y is N.
 56. The compound ofclaim 54 or 55 wherein R₂ is isopropyl and R₃ is H.
 57. The compound ofclaim 56 wherein R₁ is optionally substituted benzyl.
 58. The compoundof claim 57 wherein R₁ is methylbenzyl.
 59. The compound of claim 57wherein R₁ is trifluoromethylbenzyl.
 60. The compound of claim 57wherein benzyl is substituted with dialkylamino.
 61. The compound ofclaim 60 wherein the dialkylamino is dimethylamino.
 62. The compound ofclaim 56 where R₁ is methylenenaphthyl.
 63. The compound of claim 56where R₁ is alkyl.
 64. The compound of claim 63 wherein R₁₄ is alkyl andA is --OC(O)NH--.
 65. The compound of claim 64 whereinR₁₃ is H; R₁₄ ismethyl; and R'₂ and R'₃ are H.
 66. The compound of claim 56 wherein R₁is methyl.
 67. The compound of claim 56 wherein R₁ is3,4-methylenedioxybenzyl.
 68. The compound of claim 13:2-5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!-N- 1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-methylpropyl!acetamide;or 2-5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl!-N-1-(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-methylpropyl!acetamide.69. The compound of claim 15 wherein X is N and Y is O.
 70. The compoundof claim 15 wherein X is O and Y is N.
 71. The compound of claim 69 or70 wherein R₂ is isopropyl and R₃ is H.
 72. The compound of claim 71wherein R₁ is optionally substituted benzyl.
 73. The compound of claim72 wherein R₁ is methylbenzyl.
 74. The compound of claim 72 wherein R₁is trifluoromethylbenzyl.
 75. The compound of claim 72 wherein benzyl issubstituted with dialkylamino.
 76. The compound of claim 75 wherein thedialkylamino is dimethylamino.
 77. The compound of claim 71 where R₁ ismethylenenaphthyl.
 78. The compound of claim 71 wherein R₁ is methyl.79. The compound of claim 71 wherein R₁ is 3,4-methylenedioxybenzyl. 80.The compound of claim 20 wherein X is N and Y is O.
 81. The compound ofclaim 20 wherein X is O and Y is N.
 82. The compound of claim 80 or 81wherein R₂ is isopropyl and R₃ is H.
 83. The compound of claim 82wherein R₁ is optionally substituted benzyl.
 84. The compound of claim83 wherein R₁ is methylbenzyl.
 85. The compound of claim 83 wherein R₁is trifluoromethylbenzyl.
 86. The compound of claim 83 wherein benzyl issubstituted with dialkylamino.
 87. The compound of claim 86 wherein thedialkylamino is dimethylamino.
 88. The compound of claim 82 where R₁ ismethylenenaphthyl.
 89. The compound of claim 82 wherein R₁ is methyl.90. The compound of claim 82 wherein R₁ is 3,4-methylenedioxybenzyl. 91.The compound of claim 23 wherein X is N and Y is O.
 92. The compound ofclaim 23 wherein X is O and Y is N.
 93. The compound of claim 91 or 92wherein R₂ is isopropyl and R₃ is H.
 94. The compound of claim 93wherein R₁ is optionally substituted benzyl.
 95. The compound of claim94 wherein R₁ is methylbenzyl.
 96. The compound of claim 94 wherein R₁is trifluoromethylbenzyl.
 97. The compound of claim 94 wherein benzyl issubstituted with dialkylamino.
 98. The compound of claim 97 wherein thedialkylamino is dimethylamino.
 99. The compound of claim 93 wherein R₁is methylenenaphthyl.
 100. The compound of claim 93 wherein R₁ ismethyl.
 101. The compound of claim 93 wherein R₁ is3,4-methylenedioxybenzyl.
 102. The compound of claim 31 wherein X is Nand Y is O.
 103. The compound of claim 31 wherein X is O and Y is N.104. The compound of claim 103 wherein R₂ is isopropyl and R₃ is H. 105.The compound of claim 104 wherein R₁ is optionally substituted benzyl.106. The compound of claim 105 wherein R₁ is methylbenzyl.
 107. Thecompound of claim 105 wherein R₁ is trifluoromethylbenzyl.
 108. Thecompound of claim 105 wherein benzyl is substituted with dialkylamino.109. The compound of claim 108 wherein the dialkylamino isdimethylamino.
 110. The compound of claim 104 where R₁ ismethylenenaphthyl.
 111. The compound of claim 104 wherein R₁ is methyl.112. The compound of claim 104 wherein R₁ is 3,4-methylenedioxybenzyl.113. The compound of claim 31:1-Acetyl-3-benzylidenepiperazine-2,5-dione-N- 1(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide;or 1-Acetyl-3-(4-fluorobenzylidene)piperazine-2,5-dione-N- 1(2-5-(3-methylbenzyl)-1,3,4-oxadiazolyl!carbonyl)-2-(S)-methylpropyl!acetamide.114. The compound of claim 34 or 42 wherein X is N and Y is O.
 115. Thecompound of claim 34 or 42 wherein X is O and Y is N.
 116. The compoundof claim 114 wherein R₂ is isopropyl and R₃ is H.
 117. The compound ofclaim 116 wherein R₁ is optionally substituted benzyl.
 118. The compoundof claim 117 wherein R₁ is methylbenzyl.
 119. The compound of claim 117wherein R₁ is trifluoromethylbenzyl.
 120. The compound of claim 117wherein benzyl is substituted with dialkylamino.
 121. The compound ofclaim 120 wherein the dialkylamino is dimethylamino.
 122. The compoundof claim 116 where R₁ is methylenenaphthyl.
 123. The compound of claim116 wherein R₁ is methyl.
 124. The compound of claim 116 wherein R₁ is3,4-methylenedioxybenzyl.